JPH06157528A - 10-substituted-8,11-iminoazepino(1,2-b)isoquinoline derivative - Google Patents
10-substituted-8,11-iminoazepino(1,2-b)isoquinoline derivativeInfo
- Publication number
- JPH06157528A JPH06157528A JP33954792A JP33954792A JPH06157528A JP H06157528 A JPH06157528 A JP H06157528A JP 33954792 A JP33954792 A JP 33954792A JP 33954792 A JP33954792 A JP 33954792A JP H06157528 A JPH06157528 A JP H06157528A
- Authority
- JP
- Japan
- Prior art keywords
- group
- iminoazepino
- hydroxymethyl
- methyl
- octahydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 10-substituted-8,11-iminoazepino(1,2-b)isoquinoline Chemical class 0.000 title claims abstract description 44
- 125000002252 acyl group Chemical group 0.000 claims abstract description 21
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 16
- 125000005042 acyloxymethyl group Chemical group 0.000 claims abstract description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 4
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 abstract description 34
- 150000001875 compounds Chemical class 0.000 abstract description 17
- 239000002246 antineoplastic agent Substances 0.000 abstract description 6
- 230000003013 cytotoxicity Effects 0.000 abstract description 6
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 6
- 241000813634 Streptomyces melanovinaceus Species 0.000 abstract description 2
- 239000002207 metabolite Substances 0.000 abstract description 2
- VOUMVHRRAVBACH-UHFFFAOYSA-N Quinocarcin Natural products N12C3OCC1C=1C(OC)=CC=CC=1CC2C1N(C)C3CC1C(O)=O VOUMVHRRAVBACH-UHFFFAOYSA-N 0.000 abstract 1
- 241000187747 Streptomyces Species 0.000 abstract 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- VOUMVHRRAVBACH-RXCQEBQVSA-N quinocarcin Chemical compound C=1([C@@H]2CO[C@H]3N42)C(OC)=CC=CC=1C[C@H]4[C@@H]1N(C)[C@H]3C[C@H]1C(O)=O VOUMVHRRAVBACH-RXCQEBQVSA-N 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 26
- 239000010410 layer Substances 0.000 description 19
- 239000000126 substance Substances 0.000 description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 150000002537 isoquinolines Chemical class 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- CENNZBJWFJNNJM-UHFFFAOYSA-N 11,16-diazatetracyclo[11.2.1.02,11.04,9]hexadeca-1,3,5,7,9,12,14-heptaene Chemical class C1=CC=CC2=CC3=C(N4)C=CC4=CN3C=C21 CENNZBJWFJNNJM-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 244000309464 bull Species 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OBQUTMCLQPTELW-UHFFFAOYSA-N C1C=CC2=CN3C=CC=CC=C3C=C2C1=N Chemical class C1C=CC2=CN3C=CC=CC=C3C=C2C1=N OBQUTMCLQPTELW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 235000013736 caramel Nutrition 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- KPADFPAILITQBG-UHFFFAOYSA-N non-4-ene Chemical compound CCCCC=CCCC KPADFPAILITQBG-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 230000004565 tumor cell growth Effects 0.000 description 2
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000001088 1-naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KYNFOMQIXZUKRK-UHFFFAOYSA-N 2,2'-dithiodiethanol Chemical compound OCCSSCCO KYNFOMQIXZUKRK-UHFFFAOYSA-N 0.000 description 1
- BDZHKUAKSMWSAJ-UHFFFAOYSA-N 2-chloro-n,n-diethyl-1,1,2-trifluoroethanamine Chemical compound CCN(CC)C(F)(F)C(F)Cl BDZHKUAKSMWSAJ-UHFFFAOYSA-N 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- BURVZIMYUVKJPV-UHFFFAOYSA-N C(C)N(CC)CC.CSC.ClN1C(CCC1=O)=O Chemical compound C(C)N(CC)CC.CSC.ClN1C(CCC1=O)=O BURVZIMYUVKJPV-UHFFFAOYSA-N 0.000 description 1
- 239000012027 Collins reagent Substances 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000001727 carbonic acid monoesters Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- OOYGSFOGFJDDHP-KMCOLRRFSA-N kanamycin A sulfate Chemical compound OS(O)(=O)=O.O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N OOYGSFOGFJDDHP-KMCOLRRFSA-N 0.000 description 1
- 229960002064 kanamycin sulfate Drugs 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- MVVYGFJDUBYNTQ-UHFFFAOYSA-N n,n-diethylethanamine;methylsulfinylmethane;oxalyl dichloride Chemical compound CS(C)=O.ClC(=O)C(Cl)=O.CCN(CC)CC MVVYGFJDUBYNTQ-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- SAVQQRYWWAGSQW-UHFFFAOYSA-N n-methyl-n-(trifluoro-$l^{4}-sulfanyl)methanamine Chemical compound CN(C)S(F)(F)F SAVQQRYWWAGSQW-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000001402 nonanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- PWQOZRPSDQKNPW-UHFFFAOYSA-N pentane-1-sulfonyl chloride Chemical compound CCCCCS(Cl)(=O)=O PWQOZRPSDQKNPW-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- QHMQWEPBXSHHLH-UHFFFAOYSA-N sulfur tetrafluoride Chemical compound FS(F)(F)F QHMQWEPBXSHHLH-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は強力な細胞毒性を示し、
抗腫瘍剤としての用途が期待される新規な１０−置換−
８，１１−イミノアゼピノ［１，２−ｂ］イソキノリン
誘導体に関する。The present invention shows strong cytotoxicity,
Novel 10-Substitution-Expected to be Used as Antitumor Agent-
It relates to 8,11-iminoazepino [1,2-b] isoquinoline derivatives.
【０００２】[0002]
【従来の技術】優れた抗腫瘍剤の開発には社会からの強
力な要請があり、強力な細胞毒性を有する新規な化合物
を創製することは優れた抗腫瘍剤開発において大変重要
な位置を占めている。一般に化合物の抗腫瘍活性と抗腫
瘍スペクトルはその化学構造に大きく依存することが知
られており、既知のものと異なる新規な構造を有する細
胞毒性化合物から、現在実用に供せられている抗腫瘍剤
より優れた特徴を有する抗腫瘍剤が開発される可能性は
極めて大きい。本発明の１０−置換−８，１１−イミノ
アゼピノ［１，２−ｂ］イソキノリン誘導体は強力な細
胞毒性を示す新規な化合物である。2. Description of the Related Art There is a strong demand from society for the development of excellent antitumor agents, and the creation of novel compounds with strong cytotoxicity occupies a very important position in the development of excellent antitumor agents. ing. In general, it is known that the antitumor activity and antitumor spectrum of a compound largely depend on its chemical structure, and antitumor compounds currently available for practical use from cytotoxic compounds having a novel structure different from the known ones. The possibility of developing an anti-tumor agent with characteristics superior to that of the agent is extremely large. The 10-substituted-8,11-iminoazepino [1,2-b] isoquinoline derivative of the present invention is a novel compound showing strong cytotoxicity.
【０００３】[0003]
【発明が解決しようとする課題】本発明の目的は、強力
な細胞毒性を示し抗腫瘍剤としての用途が期待される新
規化合物である１０−置換−８，１１−イミノアゼピノ
［１，２−ｂ］イソキノリン誘導体を提供することにあ
る。The object of the present invention is 10-substituted-8,11-iminoazepino [1,2-b], which is a novel compound showing strong cytotoxicity and expected to be used as an antitumor agent. ] It is to provide an isoquinoline derivative.
【０００４】[0004]
【課題を解決するための手段】本発明は、一般式The present invention has the general formula
【０００５】[0005]
【化２】 [Chemical 2]
【０００６】（式中、Ｘは水素原子またはアシル基、Ｙ
はホルミル基、ヒドロキシメチル基、アシルオキシメチ
ル基、スルホニルオキシメチル基、またはフロロメチル
基を表す）で表される１０−置換−８，１１−イミノア
ゼピノ［１，２−ｂ］イソキノリン誘導体に関する。(In the formula, X is a hydrogen atom or an acyl group, and Y is
Represents a formyl group, a hydroxymethyl group, an acyloxymethyl group, a sulfonyloxymethyl group, or a fluoromethyl group), and a 10-substituted-8,11-iminoazepino [1,2-b] isoquinoline derivative.
【０００７】アシル基としては、ホルミル基、アセチル
基、プロピオニル基、２−メチルプロピオニル基、２，
２−ジメチルプロピオニル基、ブチリル基、ペンタノイ
ル基、ノナノイル基、クロロアセチル基、トリフロロア
セチル基、アクロイル基、クロトノイル基、シンナモイ
ル基、２−メチルアセチレン−１−カルボニル基、２−
フェニルアセチレン−１−カルボニル基、ベンゾイル
基、ｐ−フロロベンゾイル基、ｐ−クロロベンゾイル
基、ｐ−ヨードベンゾイル基、ｐ−アニソイル基、２，
４−ジクロロベンゾイル基、トルオイル基、２，４，６
−トリメチルベンゾイル基、２，４−ジメトキシベンゾ
イル基、１−ナフトイル基、２−ナフトイル基、ピリジ
ン−２−カルボニル基、ピリジン−４−カルボニル基、
チオフェン−２−カルボニル基、フラン−２−カルボニ
ル基、フェニルアセチル基、１−フェニルプロピオニル
基、２−フェニルプロピオニル基、チオフェン−２−ア
セチル基、メトキシカルボニル基、エトキシカルボニル
基、ベンジルオキシカルボニル基、ｐ−ニトロベンジル
オキシカルボニル基、アリールオキシカルボニル基、カ
ルバモイル基、Ｎ−メチルカルバモイル基、Ｎ，Ｎ−ジ
メチルカルバモイル基、Ｎ−フェニルカルバモイル基、
Ｎ−メチル−Ｎ−フェニルカルバモイル基等のアシル基
が例示できる。As the acyl group, formyl group, acetyl group, propionyl group, 2-methylpropionyl group, 2,
2-dimethylpropionyl group, butyryl group, pentanoyl group, nonanoyl group, chloroacetyl group, trifluoroacetyl group, acroyl group, crotonoyl group, cinnamoyl group, 2-methylacetylene-1-carbonyl group, 2-
Phenylacetylene-1-carbonyl group, benzoyl group, p-fluorobenzoyl group, p-chlorobenzoyl group, p-iodobenzoyl group, p-anisoyl group, 2,
4-dichlorobenzoyl group, toluoyl group, 2,4,6
-Trimethylbenzoyl group, 2,4-dimethoxybenzoyl group, 1-naphthoyl group, 2-naphthoyl group, pyridine-2-carbonyl group, pyridine-4-carbonyl group,
Thiophene-2-carbonyl group, furan-2-carbonyl group, phenylacetyl group, 1-phenylpropionyl group, 2-phenylpropionyl group, thiophen-2-acetyl group, methoxycarbonyl group, ethoxycarbonyl group, benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, aryloxycarbonyl group, carbamoyl group, N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, N-phenylcarbamoyl group,
An acyl group such as an N-methyl-N-phenylcarbamoyl group can be exemplified.
【０００８】スルホニル基は、置換もしくは無置換の炭
素数１〜５のアルカンスルホニル基または置換もしくは
無置換の芳香族スルホニル基であり、メタンスルホニル
基、エタンスルホニル基、プロパンスルホニル基、ベン
ゼンスルホニル基、ｐ−トルエンスルホニル基などを例
示できる。The sulfonyl group is a substituted or unsubstituted alkanesulfonyl group having 1 to 5 carbon atoms or a substituted or unsubstituted aromatic sulfonyl group, and is a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a benzenesulfonyl group, Examples thereof include p-toluenesulfonyl group.
【０００９】前記一般式［Ｉ］で表される１０−置換−
８，１１−イミノアゼピノ［１，２−ｂ］イソキノリン
誘導体は下記の合成工程によって製造することができ
る。10-Substitution- represented by the above general formula [I]
The 8,11-iminoazepino [1,2-b] isoquinoline derivative can be produced by the following synthetic steps.
【００１０】[0010]
【化３】 [Chemical 3]
【００１１】（式中、Ｘ′はアシル基を表す）(In the formula, X'represents an acyl group)
【００１２】［第１工程］本工程は、文献記載の方法
（H.Saito et al., Chem. Pharm. Bull., 38, 1278(199
0).)に従って、放線菌、Streptomyces melanovinaceu
s、の代謝産物であるキノカルシン(F.Tomita et al.,
J. Antibiot., 36, 463, 468 (1983).)から製造した式
［ＩＩ］で表される（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１
Ｒ，１１ａＳ）−５−ヒドロキシメチル−７−シアノ−
４−メトキシ−１３−メチル−５，７，８，９，１０，
１１，１１ａ，１２−オクタヒドロ−８，１１−イミノ
アゼピノ［１，２−ｂ］イソキノリン−１０−カルボン
酸の５位ヒドロキシメチル基をアシル化して、一般式
［ＩＩＩ］で表される（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１
１Ｒ，１１ａＳ）−５−アシルオキシメチル−７−シア
ノ−４−メトキシ−１３−メチル−５，７，８，９，１
０，１１，１１ａ，１２−オクタヒドロ−８，１１−イ
ミノアゼピノ［１，２−ｂ］イソキノリン−１０−カル
ボン酸を製造するものである。[First Step] This step is the method described in the literature (H. Saito et al., Chem. Pharm. Bull., 38 , 1278 (199).
Streptomyces melanovinaceu according to (0).)
s, a metabolite of quinocalcin (F. Tomita et al.,
J. Antibiot., 36 , 463, 468 (1983).) Represented by the formula [II] (5R, 7R, 8S, 10R, 11
R, 11aS) -5-Hydroxymethyl-7-cyano-
4-methoxy-13-methyl-5,7,8,9,10,
The 5-position hydroxymethyl group of 11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline-10-carboxylic acid is acylated to give a compound represented by the general formula [III] (5R, 7R , 8S, 10R, 1
1R, 11aS) -5-acyloxymethyl-7-cyano-4-methoxy-13-methyl-5,7,8,9,1
It is intended to produce 0,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline-10-carboxylic acid.
【００１３】導入されるアシル基としては、上で例示し
たアシル基が用いられるが、好適にはアセチル基、およ
びベンゾイル基が用いられる。これらアシル基の導入は
公知の方法(T.W.Greene, "Protective Groups in Organ
ic Synthesis", A Wiley-Interscience, New York, 198
1, pp. 10-72)によって行われる。As the acyl group to be introduced, the acyl groups exemplified above are used, but acetyl group and benzoyl group are preferably used. The introduction of these acyl groups is a known method (TW Greene, "Protective Groups in Organ
ic Synthesis ", A Wiley-Interscience, New York, 198
1, pp. 10-72).
【００１４】［第２工程］本工程は、一般式［ＩＩＩ］
で表される（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１
ａＳ）−５−アシルオキシメチル−７−シアノ−４−メ
トキシ−１３−メチル−５，７，８，９，１０，１１，
１１ａ，１２−オクタヒドロ−８，１１−イミノアゼピ
ノ［１，２−ｂ］イソキノリン−１０−カルボン酸の１
０位カルボキシル基を還元し、一般式［Ｉａ］で表され
る本発明の化合物である（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，
１１Ｒ，１１ａＳ）−５−アシルオキシメチル−７−シ
アノ−１０−ヒドロキシメチル−４−メトキシ−１３−
メチル−５，７，８，９，１０，１１，１１ａ，１２−
オクタヒドロ−８，１１−イミノアゼピノ［１，２−
ｂ］イソキノリン誘導体を製造するものである。[Second Step] This step is carried out by the general formula [III]
Represented by (5R, 7R, 8S, 10R, 11R, 11
aS) -5-acyloxymethyl-7-cyano-4-methoxy-13-methyl-5,7,8,9,10,11,
1 of 11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline-10-carboxylic acid
A compound of the present invention represented by the general formula [Ia] which is obtained by reducing the 0-position carboxyl group (5R, 7R, 8S, 10R,
11R, 11aS) -5-Acyloxymethyl-7-cyano-10-hydroxymethyl-4-methoxy-13-
Methyl-5,7,8,9,10,11,11a, 12-
Octahydro-8,11-iminoazepino [1,2-
b] to produce an isoquinoline derivative.
【００１５】カルボキシル基のヒドロキシメチル基への
還元は、一般式［ＩＩＩ］の化合物をトリエチルアミ
ン、Ｎ，Ｎ，Ｎ′，Ｎ′−テトラメチルエチレンジアミ
ン、１，５−ジアザビシクロ［４．３．０］ノン−５−
エン、１，４−ジアザビシクロ［２．２．２］オクタ
ン、１，８−ジアザビシクロ［５．４．０］ウンデク−
７−エン、ピリジン、４−ジメチルアミノピリジン等の
３級アミン存在下、クロロ炭酸メチル、クロロ炭酸エチ
ル、クロロ炭酸イソプロピル、クロロ炭酸ベンジル等の
クロロ炭酸エステルと一旦処理して、そのカルボキシル
基をカルボン酸と炭酸モノエステルとの混合酸無水物に
導き、このものを水素化ホウ素リチウム、水素化ホウ素
ナトリウム等で還元する方法によって行われる。混合酸
無水物の製造とその還元は溶媒中で行われ、用いられる
溶媒としては反応に関与しないものであれば如何なるも
のも使用できるが、好適にはエーテル、テトラヒドロフ
ラン、ジオキサン、１，２−ジメトキシエタン等のエー
テル系溶媒が用いられる。混合酸無水物の製造とその還
元は−５０℃から１００℃で円滑に進行する。The reduction of the carboxyl group to a hydroxymethyl group is carried out by converting the compound of the general formula [III] into triethylamine, N, N, N ', N'-tetramethylethylenediamine and 1,5-diazabicyclo [4.3.0]. Non-5
Ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-
In the presence of a tertiary amine such as 7-ene, pyridine or 4-dimethylaminopyridine, it is once treated with a chlorocarbonic acid ester such as methyl chlorocarbonate, ethyl chlorocarbonate, isopropyl chlorocarbonate or benzyl chlorocarbonate to convert the carboxyl group to a carboxyl group. It is carried out by a method of leading to a mixed acid anhydride of an acid and a carbonic acid monoester, and reducing this with lithium borohydride, sodium borohydride or the like. Production of the mixed acid anhydride and its reduction are carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably ether, tetrahydrofuran, dioxane, 1,2-dimethoxy. An ether solvent such as ethane is used. The production of the mixed acid anhydride and its reduction proceed smoothly at -50 ° C to 100 ° C.
【００１６】［第３工程］本工程は、一般式［Ｉａ］で
表される（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａ
Ｓ）−５−アシルオキシメチル−７−シアノ−１０−ヒ
ドロキシメチル−４−メトキシ−１３−メチル−５，
７，８，９，１０，１１，１１ａ，１２−オクタヒドロ
−８，１１−イミノアゼピノ［１，２−ｂ］イソキノリ
ン誘導体の５位アシルオキシメチル基のアシル基を除去
して、式［Ｉｂ］で表される本発明の化合物である（５
Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａＳ）−７−シ
アノ−５，１０−ビス（ヒドロキシメチル）−４−メト
キシ−１３−メチル−５，７，８，９，１０，１１，１
１ａ，１２−オクタヒドロ−８，１１−イミノアゼピノ
［１，２−ｂ］イソキノリンを製造するものである。[Third Step] This step is represented by the general formula [Ia] (5R, 7R, 8S, 10R, 11R, 11a).
S) -5-Acyloxymethyl-7-cyano-10-hydroxymethyl-4-methoxy-13-methyl-5.
7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline derivative is represented by the formula [Ib] by removing the acyl group of 5-acyloxymethyl group. (5)
R, 7R, 8S, 10R, 11R, 11aS) -7-Cyano-5,10-bis (hydroxymethyl) -4-methoxy-13-methyl-5,7,8,9,10,11,1
1a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline.
【００１７】アシル基の除去は、用いられているアシル
基の種類に応じて公知の方法(T.W.Greene, "Protective
Groups in Organic Synthesis", A Wiley-Interscienc
e, New York, 1981, pp. 10-72)によって行われる。The acyl group can be removed by a known method (TW Greene, "Protective Protection", depending on the type of the acyl group used.
Groups in Organic Synthesis ", A Wiley-Interscienc
e, New York, 1981, pp. 10-72).
【００１８】[0018]
【化４】 [Chemical 4]
【００１９】（式中、Ｘ′はアシル基を表す）(In the formula, X'represents an acyl group)
【００２０】［第４工程］本工程は、一般式［Ｉａ］で
表される（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａ
Ｓ）−５−アシルオキシメチル−７−シアノ−１０−ヒ
ドロキシメチル−４−メトキシ−１３−メチル−５，
７，８，９，１０，１１，１１ａ，１２−オクタヒドロ
−８，１１−イミノアゼピノ［１，２−ｂ］イソキノリ
ン誘導体の１０位ヒドロキシメチル基を酸化して、本発
明の化合物である一般式［Ｉｃ］で表される（５Ｒ，７
Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａＳ）−５−アシルオ
キシメチル−７−シアノ−１０−ホルミル−４−メトキ
シ−１３−メチル−５，７，８，９，１０，１１，１１
ａ，１２−オクタヒドロ−８，１１−イミノアゼピノ
［１，２−ｂ］イソキノリン誘導体を製造するものであ
る。[Fourth Step] This step is represented by the general formula [Ia] (5R, 7R, 8S, 10R, 11R, 11a).
S) -5-Acyloxymethyl-7-cyano-10-hydroxymethyl-4-methoxy-13-methyl-5.
The 7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline derivative is oxidized by the 10-position hydroxymethyl group to give a compound of the present invention represented by the general formula Ic] (5R, 7
R, 8S, 10R, 11R, 11aS) -5-Acyloxymethyl-7-cyano-10-formyl-4-methoxy-13-methyl-5,7,8,9,10,11,11
It is intended to produce an a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline derivative.
【００２１】ヒドロキシメチル基のアルデヒド基への酸
化は、Ｃｏｌｌｉｎｓ試薬、ピリジニウムクロロクロメ
ート、ピリジニウムジクロメート、三酸化イオウ・ピリ
ジンコンプレックス−ジメチルスルホキシド−トリエチ
ルアミン、塩化オキザリル−ジメチルスルホキシド−ト
リエチルアミン、トリアセトキシペルヨージナン（Ｄｅ
ｓｓ−Ｍａｒｔｉｎ試薬）、Ｎ−クロロコハク酸イミド
−ジメチルスルフィド−トリエチルアミン、等を用いて
行われるが、好適にはトリアセトキシペルヨージナンが
用いられる。反応は溶媒中で行われ、用いられる溶媒と
しては反応に関与しないものであれば如何なるものも用
いられるが、好適には、ジクロロメタン、クロロホルム
等のハロゲン化炭化水素系溶媒が用いられる。反応は−
５０℃から５０℃で円滑に進行する。Oxidation of hydroxymethyl groups to aldehyde groups is accomplished by Collins reagent, pyridinium chlorochromate, pyridinium dichromate, sulfur trioxide / pyridine complex-dimethyl sulfoxide-triethylamine, oxalyl chloride-dimethyl sulfoxide-triethylamine, triacetoxy periodinane. (De
ss-Martin reagent), N-chlorosuccinimide-dimethylsulfide-triethylamine, etc., but preferably triacetoxy periodinane is used. The reaction is carried out in a solvent, and any solvent that does not participate in the reaction can be used, but halogenated hydrocarbon solvents such as dichloromethane and chloroform are preferably used. The reaction is-
It progresses smoothly at 50 ° C to 50 ° C.
【００２２】[0022]
【化５】 [Chemical 5]
【００２３】（式中、Ｘ′はアシル基、Ｙ′はアシル基
を表す）(In the formula, X'represents an acyl group and Y'represents an acyl group)
【００２４】［第５工程］本工程は、一般式［Ｉａ］で
表される（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａ
Ｓ）−５−アシルオキシメチル−７−シアノ−１０−ヒ
ドロキシメチル−４−メトキシ−１３−メチル−５，
７，８，９，１０，１１，１１ａ，１２−オクタヒドロ
−８，１１−イミノアゼピノ［１，２−ｂ］イソキノリ
ン誘導体の１０位ヒドロキシメチル基をアシル化し、本
発明の化合物である一般式［Ｉｄ］で表される（５Ｒ，
７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａＳ）−５，１０−
ビス（アシルオキシメチル）−７−シアノ−４−メトキ
シ−１３−メチル−５，７，８，９，１０，１１，１１
ａ，１２−オクタヒドロ−８，１１−イミノアゼピノ
［１，２−ｂ］イソキノリン誘導体を製造するものであ
る。[Fifth Step] This step is represented by the general formula [Ia] (5R, 7R, 8S, 10R, 11R, 11a).
S) -5-Acyloxymethyl-7-cyano-10-hydroxymethyl-4-methoxy-13-methyl-5.
The 7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline derivative is acylated at the 10-position hydroxymethyl group to give a compound of the formula [Id ] (5R,
7R, 8S, 10R, 11R, 11aS) -5, 10-
Bis (acyloxymethyl) -7-cyano-4-methoxy-13-methyl-5,7,8,9,10,11,11
It is intended to produce an a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline derivative.
【００２５】導入されるアシル基としては、上で例示し
たものが用いられるが、好適には、アセチル基およびベ
ンゾイル基が用いられる。アシル基の導入は公知の方法
(T.W.Greene, "Protective Groups in Organic Synthes
is", A Wiley-Interscience,New York, 1981, pp. 10-7
2)によって行われる。As the acyl group to be introduced, those exemplified above are used, but preferably an acetyl group and a benzoyl group are used. A known method for introducing an acyl group
(TWGreene, "Protective Groups in Organic Synthes
is ", A Wiley-Interscience, New York, 1981, pp. 10-7
2).
【００２６】[0026]
【化６】 [Chemical 6]
【００２７】（式中、Ｘ′はアシル基、Ｚは置換もしく
は無置換の炭素数１〜５のアルキル基または置換もしく
は無置換のアリール基を表す）(In the formula, X'represents an acyl group, Z represents a substituted or unsubstituted alkyl group having 1 to 5 carbon atoms, or a substituted or unsubstituted aryl group)
【００２８】［第６工程］本工程は、一般式［Ｉａ］で
表される（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａ
Ｓ）−５−アシルオキシメチル−７−シアノ−１０−ヒ
ドロキシメチル−４−メトキシ−１３−メチル−５，
７，８，９，１０，１１，１１ａ，１２−オクタヒドロ
−８，１１−イミノアゼピノ［１，２−ｂ］イソキノリ
ン誘導体の１０位ヒドロキシメチル基をスルホニル化し
て、本発明の化合物である一般式［Ｉｅ］で表される
（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａＳ）−５
−アシルオキシメチル−７−シアノ−４−メトキシ−１
３−メチル−１０−スルホニルオキシメチル−５，７，
８，９，１０，１１，１１ａ，１２−オクタヒドロ−
８，１１−イミノアゼピノ［１，２−ｂ］イソキノリン
誘導体を製造するものである。[Sixth Step] This step is represented by the general formula [Ia] (5R, 7R, 8S, 10R, 11R, 11a).
S) -5-Acyloxymethyl-7-cyano-10-hydroxymethyl-4-methoxy-13-methyl-5.
The 7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline derivative is sulfonylated at the 10-position hydroxymethyl group to give a compound of the present invention represented by the general formula: Ie] represented by (5R, 7R, 8S, 10R, 11R, 11aS) -5
-Acyloxymethyl-7-cyano-4-methoxy-1
3-methyl-10-sulfonyloxymethyl-5,7,
8,9,10,11,11a, 12-octahydro-
It is intended to produce an 8,11-iminoazepino [1,2-b] isoquinoline derivative.
【００２９】ヒドロキシメチル基のスルホニル化は、ト
リエチルアミン、Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチルエ
チレンジアミン、１，５−ジアザビシクロ［４．３．
０］ノン−５−エン、１，４−ジアザビシクロ［２．
２．２］オクタン、１，８−ジアザビシクロ［５．４．
０］ウンデク−７−エン、ピリジン、４−ジメチルアミ
ノピリジン、等の３級アミン存在下、塩化アルカンスル
ホニルまたは塩化アレーンスルホニルを用いて行われ
る。用いられる塩化アルカンスルホニルおよび塩化アレ
ーンスルホニルとしては、塩化メタンスルホニル、塩化
エタンスルホニル、塩化プロパンスルホニル、塩化ペン
タンスルホニル、塩化トリフロロメタンスルホニル、塩
化ベンゼンスルホニル、塩化ｐ−トルエンスルホニル等
が例示されるが、好適には、塩化メタンスルホニルが用
いられる。反応は溶媒中で行われ、用いられる溶媒とし
ては反応に関与しないものであれば如何なるものも使用
できるが、好適には、ジクロロメタン、クロロホルム等
のハロゲン化炭化水素系溶媒が用いられる。反応は−５
０℃から５０℃で円滑に進行する。The sulfonylation of the hydroxymethyl group can be carried out by triethylamine, N, N, N ', N'-tetramethylethylenediamine, 1,5-diazabicyclo [4.3.
0] Non-5-ene, 1,4-diazabicyclo [2.
2.2] Octane, 1,8-diazabicyclo [5.4.
[0] Undec-7-ene, pyridine, 4-dimethylaminopyridine and the like in the presence of a tertiary amine, using alkanesulfonyl chloride or arenesulfonyl chloride. Examples of the alkanesulfonyl chloride and arenesulfonyl chloride used include methanesulfonyl chloride, ethanesulfonyl chloride, propanesulfonyl chloride, pentanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride. Suitably methanesulfonyl chloride is used. The reaction is carried out in a solvent, and any solvent that does not participate in the reaction can be used, but a halogenated hydrocarbon solvent such as dichloromethane or chloroform is preferably used. Reaction is -5
Proceeds smoothly at 0 ° C to 50 ° C.
【００３０】[0030]
【化７】 [Chemical 7]
【００３１】（式中、Ｘ′はアシル基を表す）(In the formula, X'represents an acyl group)
【００３２】［第７工程］本工程は、一般式［Ｉａ］で
表される（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａ
Ｓ）−５−アシルオキシメチル−７−シアノ−１０−ヒ
ドロキシメチル−４−メトキシ−１３−メチル−５，
７，８，９，１０，１１，１１ａ，１２−オクタヒドロ
−８，１１−イミノアゼピノ［１，２−ｂ］イソキノリ
ン誘導体の１０位ヒドロキシメチル基をフッ素化して、
本発明の化合物である一般式［Ｉｆ］で表される（５
Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａＳ）−５−ア
シルオキシメチル−７−シアノ−１０−フロロメチル−
４−メトキシ−１３−メチル−５，７，８，９，１０，
１１，１１ａ，１２−オクタヒドロ−８，１１−イミノ
アゼピノ［１，２−ｂ］イソキノリン誘導体を製造する
ものである。[Seventh Step] This step is represented by the general formula [Ia] (5R, 7R, 8S, 10R, 11R, 11a).
S) -5-Acyloxymethyl-7-cyano-10-hydroxymethyl-4-methoxy-13-methyl-5.
Fluorinating the 10-position hydroxymethyl group of the 7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline derivative,
The compound of the present invention is represented by the general formula [If] (5
R, 7R, 8S, 10R, 11R, 11aS) -5-acyloxymethyl-7-cyano-10-fluoromethyl-
4-methoxy-13-methyl-5,7,8,9,10,
It is intended to produce an 11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline derivative.
【００３３】ヒドロキシメチル基のフッ素化は、フッ化
水素−ピリジン、１−ジエチルアミノ−１，１，２−ト
リフロロ−２−クロロエタン、四フッ化硫黄、ジエチル
アミノイオウトリフロリド、ジメチルアミノイオウトリ
フロリド、テトラブチルアンモニウムフロリド−メタン
スルホニルフロリド、テトラブチルアンモニウムフロリ
ド−ｐ−トルエンスルホニルフロリド等が例示される
が、好適には、ジエチルアミノイオウトリフロリドが用
いられる。反応は溶媒中で行われ、用いられる溶媒とし
ては反応に関与しないものであれば如何なるものも使用
できるが、好適には、ジクロロメタン、クロロホルム等
のハロゲン化炭化水素系溶媒が用いられる。反応は−５
０℃から５０℃で円滑に進行する。Fluorination of the hydroxymethyl group can be carried out by hydrogen fluoride-pyridine, 1-diethylamino-1,1,2-trifluoro-2-chloroethane, sulfur tetrafluoride, diethylaminosulfur trifluoride, dimethylaminosulfur trifluoride. , Tetrabutylammonium fluoride-methanesulfonyl fluoride, tetrabutylammonium fluoride-p-toluenesulfonyl fluoride and the like are exemplified, but diethylaminosulfur trifluoride is preferably used. The reaction is carried out in a solvent, and any solvent that does not participate in the reaction can be used, but a halogenated hydrocarbon solvent such as dichloromethane or chloroform is preferably used. Reaction is -5
Proceeds smoothly at 0 ° C to 50 ° C.
【００３４】[0034]
【発明の効果】以上のようにして得られる前記式［Ｉ
ｂ］並びに前記一般式［Ｉａ］、［Ｉｃ］、［Ｉｄ］、
［Ｉｅ］および［Ｉｆ］で表される１０−置換−８，１
１−イミノアゼピノ［１，２−ｂ］イソキノリン誘導体
は、悪性腫瘍細胞増殖抑制試験により、これらの化合物
が強力な細胞毒性を示し、抗腫瘍剤としての用途を有す
ることが確認された。The above formula [I obtained as described above
b] and the general formulas [Ia], [Ic], [Id],
10-Substitution-8,1 represented by [Ie] and [If]
The 1-iminoazepino [1,2-b] isoquinoline derivative was confirmed by a malignant tumor cell growth inhibitory test that these compounds exhibited strong cytotoxicity and had use as an antitumor agent.
【００３５】[0035]
【実施例】以下参考例、実施例及び試験例により本発明
を詳細に説明するが、本発明はこれらに限定されるもの
でないことは言うまでもない。The present invention will be described in detail below with reference to Reference Examples, Examples and Test Examples, but it goes without saying that the present invention is not limited to these.
【００３６】参考例１Reference Example 1
【００３７】[0037]
【化８】 [Chemical 8]
【００３８】文献記載の方法(H.Saito et al., Chem. P
harm. Bull., 38, 1278 (1990).)に従ってキノカルシン
(F.Tomita et al., J. Antibiot., 36, 463, 468 (198
3).)から調製した（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１
Ｒ，１１ａＳ）−７−シアノ−５−ヒドロキシメチル−
４−メトキシ−１３−メチル−５，７，８，９，１０，
１１，１１ａ，１２−オクタヒドロ−８，１１−イミノ
アゼピノ［１，２−ｂ］イソキノリン−１０−カルボン
酸（３．７３ｇ，１０ｍｍｏｌ）をピリジン（５０ｍ
ｌ）に溶解し、０℃に冷却した。これに無水酢酸（３．
９４ｍｌ， ４２ｍｍｏｌ）およびＮ，Ｎ−ジメチルア
ミノピリジン（５０．０ｍｇ， ０．４１ｍｍｏｌ）を
加えた。０℃で攪拌後徐々に昇温し、室温で１０時間攪
拌した。溶媒を減圧留去し、残渣をシリカゲルカラムク
ロマトグラフィー（ヘキサン：酢酸エチル＝ １：２）
で精製し、（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１
ａＳ）−５−アセトキシメチル−７−シアノ−４−メト
キシ−１３−メチル−５，７，８，９，１０，１１，１
１ａ，１２−オクタヒドロ−８，１１−イミノアゼピノ
［１，２−ｂ］イソキノリン−１０−カルボン酸を無色
カラメル（２．２５ｇ，５６％）として得た。Methods described in the literature (H. Saito et al., Chem. P
harm. Bull., 38 , 1278 (1990).)
(F.Tomita et al., J. Antibiot., 36, 463, 468 (198
3).) Prepared from (5R, 7R, 8S, 10R, 11
R, 11aS) -7-Cyano-5-hydroxymethyl-
4-methoxy-13-methyl-5,7,8,9,10,
11,11a, 12-Octahydro-8,11-iminoazepino [1,2-b] isoquinoline-10-carboxylic acid (3.73 g, 10 mmol) was added to pyridine (50 m).
It was dissolved in l) and cooled to 0 ° C. Acetic anhydride (3.
94 ml, 42 mmol) and N, N-dimethylaminopyridine (50.0 mg, 0.41 mmol) were added. After stirring at 0 ° C., the temperature was gradually raised, and the mixture was stirred at room temperature for 10 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 2).
Purified with (5R, 7R, 8S, 10R, 11R, 11
aS) -5-acetoxymethyl-7-cyano-4-methoxy-13-methyl-5,7,8,9,10,11,1
1a, 12-Octahydro-8,11-iminoazepino [1,2-b] isoquinoline-10-carboxylic acid was obtained as colorless caramel (2.25 g, 56%).
【００３９】 [α]D 20 = +17.3° (c= 0.37, CHCl3) IR (KBr, cm-1) 3700-2800, 17351 H-NMR (400MHz, C6D6) δ： 1.54 (3H, s, -COCH3) 1.73 (1H, dd, J= 13.2, 9.7 Hz, 9-H) 2.14 (3H, s, =N-CH3) 2.24 (1H, br d, J= 14.7 Hz, 12-H) 2.36-2.50 (2H, m, 9-H and 12-H) 2.80 (1H, br d, J= 5.0 Hz, 8-H) 2.98-3.03 (2H, m, 10-H and 11a-H) 3.13 (3H, s, -OCH3) 3.30 (1H, br s, 11-H) 3.46 (1H, d, J= 1.9 Hz, 7-H) 4.06 (1H, dd, J= 10.9, 5.0 Hz, 6-H) 4.45 (1H, dd, J= 10.9, 3.0 Hz, 6-H) 4.60 (1H, dd, J= 5.0, 3.0 Hz, 5-H) 6.31 (1H, d, J= 8.0 Hz, 3-H) 6.55 (1H, d, J= 8.0 Hz, 1-H) 6.98 (1H, t, J= 8.0 Hz, 2-H) MS (m/z) 399 (M+), 373 (M-CN+), 326 (M-CH2OAc+) HRMS (m/z) M+ (C21H25N3O5) 測定値 399.1789 計算値 399.1792[Α] D 20 = + 17.3 ° (c = 0.37, CHCl 3 ) IR (KBr, cm −1 ) 3700-2800, 1735 1 H-NMR (400MHz, C 6 D 6 ) δ: 1.54 (3H , s, -COCH 3 ) 1.73 (1H, dd, J = 13.2, 9.7 Hz, 9-H) 2.14 (3H, s, = N-CH 3 ) 2.24 (1H, br d, J = 14.7 Hz, 12- H) 2.36-2.50 (2H, m, 9-H and 12-H) 2.80 (1H, br d, J = 5.0 Hz, 8-H) 2.98-3.03 (2H, m, 10-H and 11a-H) 3.13 (3H, s, -OCH 3 ) 3.30 (1H, br s, 11-H) 3.46 (1H, d, J = 1.9 Hz, 7-H) 4.06 (1H, dd, J = 10.9, 5.0 Hz, 6 -H) 4.45 (1H, dd, J = 10.9, 3.0 Hz, 6-H) 4.60 (1H, dd, J = 5.0, 3.0 Hz, 5-H) 6.31 (1H, d, J = 8.0 Hz, 3- H) 6.55 (1H, d, J = 8.0 Hz, 1-H) 6.98 (1H, t, J = 8.0 Hz, 2-H) MS (m / z) 399 (M + ), 373 (M-CN + ), 326 (M-CH 2 OAc + ) HRMS (m / z) M + (C 21 H 25 N 3 O 5 ) Measured 399.1789 Calculated 399.1792
【００４０】参考例２Reference Example 2
【００４１】[0041]
【化９】 [Chemical 9]
【００４２】文献記載の方法(H.Saito et al., Chem. P
harm. Bull., 38, 1278 (1990).)に従ってキノカルシン
(F.Tomita et al., J. Antibiot., 36, 463, 468 (198
3).)から調製した（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１
Ｒ，１１ａＳ）−７−シアノ−５−ヒドロキシメチル−
４−メトキシ−１３−メチル−５，７，８，９，１０，
１１，１１ａ，１２−オクタヒドロ−８，１１−イミノ
アゼピノ［１，２−ｂ］イソキノリン−１０−カルボン
酸（５１．３ｍｇ， ０．１４ｍｍｏｌ）のピリジン溶
液（２．０ｍｌ）に氷冷下塩化ベンゾイル（０．０６７
ｍｌ， ０．５８ｍｍｏｌ）を加え、２時間攪拌した。
水（５．０ｍｌ）を加え、ジクロロメタンで抽出した。
抽出液を無水硫酸マグネシウムで乾燥し、溶媒を留去し
た。残渣をシリカゲルカラムクロマトグラフィー（ヘキ
サン：酢酸エチル＝ １：２）で精製し、（５Ｒ，７
Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａＳ）−５−ベンゾイ
ルオキシメチル−７−シアノ−４−メトキシ−１３−メ
チル−５，７，８，９，１０，１１，１１ａ，１２−オ
クタヒドロ−８，１１−イミノアゼピノ［１，２−ｂ］
イソキノリン−１０−カルボン酸を白色アモルファス粉
末（２１．１ｍｇ， ３３％）として得た。Methods described in the literature (H. Saito et al., Chem. P
harm. Bull., 38, 1278 (1990).)
(F.Tomita et al., J. Antibiot., 36, 463, 468 (198
3).) Prepared from (5R, 7R, 8S, 10R, 11
R, 11aS) -7-Cyano-5-hydroxymethyl-
4-methoxy-13-methyl-5,7,8,9,10,
Benzoyl chloride (2.0 ml) of 11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline-10-carboxylic acid (51.3 mg, 0.14 mmol) in pyridine (2.0 ml) was cooled with ice. 0.067
ml, 0.58 mmol) was added and stirred for 2 hours.
Water (5.0 ml) was added and the mixture was extracted with dichloromethane.
The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2), (5R, 7
R, 8S, 10R, 11R, 11aS) -5-Benzoyloxymethyl-7-cyano-4-methoxy-13-methyl-5,7,8,9,10,11,11a, 12-octahydro-8,11 -Iminoazepino [1,2-b]
Isoquinoline-10-carboxylic acid was obtained as a white amorphous powder (21.1 mg, 33%).
【００４３】 [α]D 20 = -5.7° (c= 0.33, CHCl3) IR (CHCl3, cm-1) 3500-2500, 17111 H NMR (400MHz, C6D6) δ: 1.81 (1H, dd, J= 13.3, 9.6 Hz, 9-H) 2.07 (3H, s, =N-CH3) 2.17 (1H, dd, J= 14.6, 1.8 Hz, 12-H) 2.29 (1H, dd, J= 14.6, 11.5 Hz, 12-H) 2.44 (1H, dd, J= 13.3, 11.8 Hz, 9-H) 2.71 (1H, m, 8-H) 2.80 (1H, m, 10-H) 3.02 (1H, dt, J= 11.5, 1.8 Hz, 11a-H) 3.11 (3H, s, -OCH3) 3.14 (1H, br s, 11-H) 3.52 (1H, d, J= 2.7 Hz, 7-H) 4.38 (1H, dd, J= 10.9, 4.0 Hz, 6-H) 4.73 (1H, dd, J= 4.0, 3.3 Hz, 5-H) 4.78 (1H, dd, J= 10.9, 3.3 Hz, 6-H) 6.34 (1H, d, J= 8.3 Hz, 3-H) 6.57 (1H, d, J= 8.3 Hz, 1-H) 7.00 (1H, t, J= 8.3 Hz, 2-H) 6.95-7.05 (3H, m, Ar-H) 8.00 (2H, dd, J= 8.3, 1.4 Hz, Ar-H) MS (m/z) 461 (M+), 435 (M-CN+), 326 (M-CH2OCOC6H5) HRMS (m/z) M+ (C26H27N3O5) 測定値 461.1947 計算値 461.1948[Α] D 20 = -5.7 ° (c = 0.33, CHCl 3 ) IR (CHCl 3 , cm -1 ) 3500-2500, 1711 1 H NMR (400 MHz, C 6 D 6 ) δ: 1.81 (1H , dd, J = 13.3, 9.6 Hz, 9-H) 2.07 (3H, s, = N-CH 3 ) 2.17 (1H, dd, J = 14.6, 1.8 Hz, 12-H) 2.29 (1H, dd, J = 14.6, 11.5 Hz, 12-H) 2.44 (1H, dd, J = 13.3, 11.8 Hz, 9-H) 2.71 (1H, m, 8-H) 2.80 (1H, m, 10-H) 3.02 (1H , dt, J = 11.5, 1.8 Hz, 11a-H) 3.11 (3H, s, -OCH 3 ) 3.14 (1H, br s, 11-H) 3.52 (1H, d, J = 2.7 Hz, 7-H) 4.38 (1H, dd, J = 10.9, 4.0 Hz, 6-H) 4.73 (1H, dd, J = 4.0, 3.3 Hz, 5-H) 4.78 (1H, dd, J = 10.9, 3.3 Hz, 6-H) ) 6.34 (1H, d, J = 8.3 Hz, 3-H) 6.57 (1H, d, J = 8.3 Hz, 1-H) 7.00 (1H, t, J = 8.3 Hz, 2-H) 6.95-7.05 ( 3H, m, Ar-H) 8.00 (2H, dd, J = 8.3, 1.4 Hz, Ar-H) MS (m / z) 461 (M + ), 435 (M-CN + ), 326 (M-CH 2 OCOC 6 H 5 ) HRMS (m / z) M + (C 26 H 27 N 3 O 5 ) Measured value 461.1947 Calculated value 461.1948
【００４４】実施例１Example 1
【００４５】[0045]
【化１０】 [Chemical 10]
【００４６】窒素気流下、０℃で（５Ｒ，７Ｒ，８Ｓ，
１０Ｒ，１１Ｒ，１１ａＳ）−５−アセトキシメチル−
７−シアノ−４−メトキシ−１３−メチル−５，７，
８，９，１０，１１，１１ａ，１２−オクタヒドロ−
８，１１−イミノアゼピノ［１，２−ｂ］イソキノリン
−１０−カルボン酸（１０９ｍｇ， ０．２７ｍｍｏ
ｌ）のテトラヒドロフラン溶液（１０ｍｌ）にトリエチ
ルアミン（０．０８４ｍｌ，０．６０ｍｍｏｌ）および
クロロ炭酸イソプロピル（０．０８４ｍｌ，０．６０ｍ
ｍｏｌ）を加え４時間攪拌した。これに水素化ホウ素ナ
トリウム（１０２ｍｇ， ２．７ｍｍｏｌ）の水溶液
（１．５ｍｌ）を加え、攪拌しながら室温まで昇温し、
さらに２時間攪拌した。反応混合物に水（４．０ｍｌ）
を加え、酢酸エチル（５０ｍｌで２回）で抽出した。抽
出液を飽和食塩水（５０ｍｌ）で洗い無水硫酸マグネシ
ウムで乾燥後、溶媒を留去した。残渣をシリカゲルカラ
ムクロマトグラフィー（ヘキサン：酢酸エチル＝ １：
２）で精製し、（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，
１１ａＳ）−５−アセトキシメチル−７−シアノ−１０
−ヒドロキシメチル−４−メトキシ−１３−メチル−
５，７，８，９，１０，１１，１１ａ，１２−オクタヒ
ドロ−８，１１−イミノアゼピノ［１，２−ｂ］イソキ
ノリンを無色アモルファス粉末（８５．１ｍｇ， ８１
％）として得た。Under a nitrogen stream at 0 ° C. (5R, 7R, 8S,
10R, 11R, 11aS) -5-acetoxymethyl-
7-cyano-4-methoxy-13-methyl-5,7,
8,9,10,11,11a, 12-octahydro-
8,11-Iminoazepino [1,2-b] isoquinoline-10-carboxylic acid (109 mg, 0.27 mmo
1) in a solution of tetrahydrofuran (10 ml) in triethylamine (0.084 ml, 0.60 mmol) and isopropyl chlorocarbonate (0.084 ml, 0.60 m).
(mol) was added and stirred for 4 hours. An aqueous solution (1.5 ml) of sodium borohydride (102 mg, 2.7 mmol) was added thereto, and the temperature was raised to room temperature with stirring,
It was stirred for another 2 hours. Water (4.0 ml) in the reaction mixture
Was added, and the mixture was extracted with ethyl acetate (50 ml × 2). The extract was washed with saturated brine (50 ml) and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Purified in 2), (5R, 7R, 8S, 10R, 11R,
11aS) -5-acetoxymethyl-7-cyano-10
-Hydroxymethyl-4-methoxy-13-methyl-
5,7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline as colorless amorphous powder (85.1 mg, 81
%).
【００４７】 [α]D 20 = +29.2゜ (c= 1.28, CHCl3) IR (neat, cm-1) 3450, 2950, 2860, 2290, 1740, 1600, 1480, 1380, 1260, 1230, 1040, 910, 7301 H NMR (400MHz, C6D6) δ: 1.18 (br s, 1H, -OH) 1.41 (ddd, J= 12.8, 6.4, 5.5 Hz, 1H, C9-H) 1.60 (s, 3H, -OCOCH3) 1.64 (dd, J= 12.8, 9.0 Hz, 1H, C9-H) 2.13 (dd, J= 14.5, 2.3 Hz, 1H, C12-H) 2.23 (dddd, J= 9.0, 7.8, 6.5, 5.5 Hz, 1H, C10-H) 2.30 (s, 3H, =N-CH3) 2.47 (dd, J= 14.5, 12.0 Hz, 1H, C12-H) 2.61 (s, 1H, C11-H) 2.87 (dd, J= 6.4, 2.4 Hz, 1H, C8-H) 3.09 (dd, J= 12.0, 2.3 Hz, 1H, C11a-H) 3.14 (s, 3H, -OCH3) 3.27 (dd, J= 9.9, 7.8 Hz, 1H, -CH 2OH) 3.34 (dd, J= 9.9, 6.5 Hz, 1H, -CH 2OH) 3.51 (d, J= 2.4 Hz, 1H, C7-H) 4.12 (dd, J= 10.9, 4.9 Hz, 1H, -CH 2OAc) 4.52 (dd, J= 10.9, 3.0 Hz, 1H, -CH 2OAc) 4.65 (dd, J= 4.9, 3.0 Hz, 1H, C5-H) 6.33 (d, J= 8.0 Hz, 1H, C3-H) 6.61 (d, J= 8.0 Hz, 1H, C1-H) 7.01 (t, J= 8.0 Hz, 1H, C2-H) MS (m/z) 385 (M+), 312 (M-CH2OAc+) HRMS (m/z) M+ (C21H27N3O4) 測定値 385.2007 計算値 385.2000[Α] D 20 = + 29.2 ° (c = 1.28, CHCl 3 ) IR (neat, cm −1 ) 3450, 2950, 2860, 2290, 1740, 1600, 1480, 1380, 1260, 1230, 1040, 910, 730 1 H NMR (400MHz, C 6 D 6 ) δ: 1.18 (br s, 1H, -OH) 1.41 (ddd, J = 12.8, 6.4, 5.5 Hz, 1H, C 9 -H) 1.60 (s, 3H, -OCOCH 3 ) 1.64 (dd, J = 12.8, 9.0 Hz, 1H, C 9 -H) 2.13 (dd, J = 14.5, 2.3 Hz, 1H, C 12 -H) 2.23 (dddd, J = 9.0, 7.8, 6.5, 5.5 Hz, 1H, C 10 -H) 2.30 (s, 3H, = N-CH 3 ) 2.47 (dd, J = 14.5, 12.0 Hz, 1H, C 12 -H) 2.61 (s, 1H, C 11 -H) 2.87 (dd, J = 6.4, 2.4 Hz, 1H, C 8 -H) 3.09 (dd, J = 12.0, 2.3 Hz, 1H, C 11a -H) 3.14 (s, 3H, -OCH 3 ) 3.27 (dd, J = 9.9, 7.8 Hz, 1H, -C H 2 OH) 3.34 (dd, J = 9.9, 6.5 Hz, 1H, -C H 2 OH) 3.51 (d, J = 2.4 Hz, 1H, C 7 -H) 4.12 (dd, J = 10.9, 4.9 Hz, 1H, -C H 2 OAc) 4.52 (dd, J = 10.9, 3.0 Hz, 1H, -C H 2 OAc) 4.65 (dd, J = 4.9 , 3.0 Hz, 1H, C 5 -H) 6.33 (d, J = 8.0 Hz, 1H, C 3 -H) 6.61 (d, J = 8.0 Hz, 1H, C 1 -H) 7.01 (t, J = 8.0 Hz, 1H, C 2 -H) MS (m / z) 385 (M + ), 312 (M-CH 2 OAc + ) HRMS (m / z) M + (C 21 H 27 N 3 O 4 ) Measured 385.2007 Calculated 385.2000
【００４８】実施例２Example 2
【００４９】[0049]
【化１１】 [Chemical 11]
【００５０】アルゴン雰囲気下、（５Ｒ，７Ｒ，８Ｓ，
１０Ｒ，１１Ｒ，１１ａＳ）−５−ベンゾイルオキシメ
チル−７−シアノ−４−メトキシ−１３−メチル−５，
７，８，９，１０，１１，１１ａ，１２−オクタヒドロ
−８，１１−イミノアゼピノ［１，２−ｂ］イソキノリ
ン−１０−カルボン酸（２００ｍｇ， ０．４３ｍｍｏ
ｌ）をテトラヒドロフラン（４．５ｍｌ）に溶解し、ト
リエチルアミン（９１．０μｌ， ０．６５ｍｍｏｌ）
およびクロロ炭酸イソプロピル（５８．０μｌ， ０．
５２ｍｍｏｌ）を０゜ Ｃで加え、３０分攪拌した後、−
１５゜ Ｃにて水素化ほう素ナトリウム（５０．０ｍｇ，
１．３ｍｍｏｌ）の水溶液（０．５０ｍｌ）を加え
た。室温まで昇温し３０分攪拌後、反応混合物に飽和食
塩水（２０ｍｌ）及びエーテル（１０ｍｌ）を加え分液
後、水層をエーテル（１０ｍｌ）で抽出した。有機層は
合わせて無水硫酸ナトリウムで乾燥後、溶媒を留去し残
渣を分取用シリカゲル薄層クロマトグラフィー（ヘキサ
ン：酢酸エチル＝１：２）にて精製し（５Ｒ，７Ｒ，８
Ｓ，１０Ｒ，１１Ｒ，１１ａＳ）−５−ベンゾイルオキ
シメチル−７−シアノ−１０−ヒドロキシメチル−４−
メトキシ−１３−メチル−５，７，８，９，１０，１
１，１１ａ，１２−オクタヒドロ−８，１１−イミノア
ゼピノ［１，２−ｂ］イソキノリンを白色アモルファス
粉末（１７４ｍｇ， ９０％）として得た。Under an argon atmosphere, (5R, 7R, 8S,
10R, 11R, 11aS) -5-benzoyloxymethyl-7-cyano-4-methoxy-13-methyl-5.
7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline-10-carboxylic acid (200 mg, 0.43 mmo
l) was dissolved in tetrahydrofuran (4.5 ml) and triethylamine (91.0 μl, 0.65 mmol)
And isopropyl chlorocarbonate (58.0 μl, 0.
(52 mmol) at 0 ° C. and stirred for 30 minutes,
Sodium borohydride (50.0 mg,
1.3 mmol) in water (0.50 ml) was added. After warming to room temperature and stirring for 30 minutes, saturated saline (20 ml) and ether (10 ml) were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with ether (10 ml). The organic layers are combined and dried over anhydrous sodium sulfate, the solvent is evaporated, and the residue is purified by preparative silica gel thin layer chromatography (hexane: ethyl acetate = 1: 2) (5R, 7R, 8).
S, 10R, 11R, 11aS) -5-Benzoyloxymethyl-7-cyano-10-hydroxymethyl-4-
Methoxy-13-methyl-5,7,8,9,10,1
1,11a, 12-Octahydro-8,11-iminoazepino [1,2-b] isoquinoline was obtained as a white amorphous powder (174 mg, 90%).
【００５１】 [α]D 20 = +1.0゜ (c= 0.75, CHCl3) IR (neat, cm-1) 3500, 2930, 2830, 2270, 1710, 1590, 1470, 1450, 1260, 1110, 1090, 1060, 710, 5001 H NMR (400MHz, C6D6) δ: 1.10 (br s, 1H, -OH) 1.34 (ddd, J= 12.7, 6.3, 6.0 Hz, 1H, C9-H) 1.70 (dd, J= 12.7, 9.0 Hz, 1H, C9-H) 2.02 (dddd, J= 9.0, 7.7, 6.4, 6.0 Hz, 1H, C10-H) 2.08 (dd, J= 14.9, 2.3 Hz, 1H, C12-H) 2.23 (s, 3H, =N-CH3) 2.45 (dd, J= 14.9, 12.0 Hz, 1H, C12-H) 2.53 (s, 1H, C11-H) 2.80 (dd, J= 6.3, 2.4 Hz, 1H, C8-H) 3.08 (dd, J= 12.0, 2.3 Hz, 1H, C11a-H) 3.12 (dd, J= 10.0, 7.7 Hz, 1H, -CH 2OH) 3.13 (s, 3H, -OCH3) 3.17 (dd, J= 10.0, 6.4 Hz, 1H, -CH 2OH) 3.56 (d, J= 2.4 Hz, 1H, C7-H) 4.42 (dd, J= 10.9, 4.0 Hz, 1H, -CH 2OBz) 4.77 (dd, J= 4.0, 3.2 Hz, 1H, C5-H) 4.84 (dd, J= 10.9, 3.2 Hz, 1H, -CH 2OBz) 6.37 (d, J= 8.0 Hz, 1H, C3-H) 6.63 (d, J= 8.0 Hz, 1H, C1-H) 6.94-7.08 (m, 3H, -OCOC6H5) 7.04 (t, J= 8.0 Hz, 1H, C2-H) 7.98-8.04 (m, 2H, -OCOC6H5) MS (m/z) 447 (M+), 312 (M-CH2OBz+) HRMS (m/z) M+ (C26H29N3O4) 測定値 447.2144 計算値 447.2156[Α] D 20 = + 1.0 ° (c = 0.75, CHCl 3 ) IR (neat, cm −1 ) 3500, 2930, 2830, 2270, 1710, 1590, 1470, 1450, 1260, 1110, 1090, 1060, 710, 500 1 H NMR (400MHz, C 6 D 6 ) δ: 1.10 (br s, 1H, -OH) 1.34 (ddd, J = 12.7, 6.3, 6.0 Hz, 1H, C 9 -H) 1.70 ( dd, J = 12.7, 9.0 Hz, 1H, C 9 -H) 2.02 (dddd, J = 9.0, 7.7, 6.4, 6.0 Hz, 1H, C 10 -H) 2.08 (dd, J = 14.9, 2.3 Hz, 1H , C 12 -H) 2.23 (s, 3H, = N-CH 3 ) 2.45 (dd, J = 14.9, 12.0 Hz, 1H, C 12 -H) 2.53 (s, 1H, C 11 -H) 2.80 (dd , J = 6.3, 2.4 Hz, 1H, C 8 -H) 3.08 (dd, J = 12.0, 2.3 Hz, 1H, C 11a -H) 3.12 (dd, J = 10.0, 7.7 Hz, 1H, -C H 2 OH) 3.13 (s, 3H, -OCH 3 ) 3.17 (dd, J = 10.0, 6.4 Hz, 1H, -C H 2 OH) 3.56 (d, J = 2.4 Hz, 1H, C 7 -H) 4.42 (dd , J = 10.9, 4.0 Hz, 1H, -C H 2 OBz) 4.77 (dd, J = 4.0, 3.2 Hz, 1H, C 5 -H) 4.84 (dd, J = 10.9, 3.2 Hz, 1H, -C H 2 OBz) 6.37 (d, J = 8.0 Hz, 1H, C 3 -H) 6.63 (d, J = 8.0 Hz, 1H, C 1 -H) 6.94-7.08 (m, 3H, -OCOC 6 H 5 ) 7.04 (t, J = 8.0 Hz, 1H, C 2 -H) 7.98-8.04 (m, 2H, -OCOC 6 H 5 ) MS (m / z) 447 (M + ), 312 (M-C) H 2 OBz + ) HRMS (m / z) M + (C 26 H 29 N 3 O 4 ) Measured value 447.2144 Calculated value 447.2156
【００５２】実施例３Example 3
【００５３】[0053]
【化１２】 [Chemical 12]
【００５４】（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１
１ａＳ）−５−アセトキシメチル−７−シアノ−１０−
ヒドロキシメチル−４−メトキシ−１３−メチル−５，
７，８，９，１０，１１，１１ａ，１２−オクタヒドロ
−８，１１−イミノアゼピノ［１，２−ｂ］イソキノリ
ン（６４．５ｍｇ， ０．１７ｍｍｏｌ）をメタノール
（２．０ｍｌ）に溶解し、１％水酸化ナトリウム水溶液
（２．０ｍｌ）を加え、室温にて３０分攪拌した。反応
混合物に飽和食塩水（２０ｍｌ）および酢酸エチル（１
０ｍｌ）を加え分液後、水層を酢酸エチル（１０ｍｌ）
で抽出した。有機層は合わせて無水硫酸ナトリウムで乾
燥後、溶媒を留去し、残留物を分取用シリカゲル薄層ク
ロマトグラフィーにて精製し（５Ｒ，７Ｒ，８Ｓ，１０
Ｒ，１１Ｒ，１１ａＳ）−７−シアノ−５，１０−ビス
(ヒドロキシメチル)−４−メトキシ−１３−メチル−
５，７，８，９，１０，１１，１１ａ，１２−オクタヒ
ドロ−８，１１−イミノアゼピノ［１，２−ｂ］イソキ
ノリンを白色アモルファス粉末（５７．５ｍｇ， ９９
％）として得た。(5R, 7R, 8S, 10R, 11R, 1
1aS) -5-acetoxymethyl-7-cyano-10-
Hydroxymethyl-4-methoxy-13-methyl-5
7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline (64.5 mg, 0.17 mmol) was dissolved in methanol (2.0 ml) to give 1 Aqueous sodium hydroxide solution (2.0 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added with saturated saline (20 ml) and ethyl acetate (1
(0 ml) was added and the layers were separated, and the aqueous layer was washed with ethyl acetate (10 ml).
It was extracted with. The organic layers were combined, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by preparative silica gel thin layer chromatography (5R, 7R, 8S, 10).
R, 11R, 11aS) -7-Cyano-5,10-bis
(Hydroxymethyl) -4-methoxy-13-methyl-
5,7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline was converted into white amorphous powder (57.5 mg, 99
%).
【００５５】 [α]D 20 = +101゜ (c= 0.23, CH3OH) IR (KBr, cm-1) 3490, 2950, 2930, 2900, 2830, 2350, 1710, 1660, 1580, 1460, 1260, 1070, 780, 7401 H NMR (400MHz, CD3OD) δ: 1.84 (ddd, J= 13.0, 6.5, 6.2 Hz, 1H, C9-H) 2.10 (dd, J= 13.0, 9.1 Hz, 1H, C9-H) 2.49 (dd, J= 13.9, 2.4 Hz, 1H, C12-H) 2.51 (s, 3H, =N-CH3) 2.63 (dddd, J= 9.1, 8.8, 7.6, 6.2 Hz, 1H, C10-H) 2.66 (dd, J= 13.9, 11.1 Hz, 1H, C12-H) 2.91 (dd, J= 11.1, 2.4 Hz, 1H, C11a-H) 2.99 (s, 1H, C11-H) 3.42 (dd, J= 10.6, 6.9 Hz, 1H, C5-CH 2OH) 3.43 (dd, J= 6.5, 2.7 Hz, 1H, C8-H) 3.56 (dd, J= 10.6, 8.8 Hz, 1H, C10-CH 2OH) 3.62 (dd, J= 10.6, 7.6 Hz, 1H, C10-CH 2OH) 3.76 (dd, J= 10.6, 2.6 Hz, 1H, C5-CH 2OH) 3.83 (s, 3H, -OCH3) 4.20 (dd, J= 6.9, 2.6 Hz, 1H, C5-H) 4.30 (d, J= 2.7 Hz, 1H, C7-H) 6.72 (d, J= 8.0 Hz, 1H, C3-H) 6.82 (d, J= 8.0 Hz, 1H, C1-H) 7.14 (t, J= 8.0 Hz, 1H, C2-H) MS (m/z) 343 (M+), 312(M-CH2OH+) HRMS (m/z) M+ (C19H25N3O3) 測定値 343.1919 計算値 343.1894[Α] D 20 = + 101 ° (c = 0.23, CH 3 OH) IR (KBr, cm −1 ) 3490, 2950, 2930, 2900, 2830, 2350, 1710, 1660, 1580, 1460, 1260 , 1070, 780, 740 1 H NMR (400MHz, CD 3 OD) δ: 1.84 (ddd, J = 13.0, 6.5, 6.2 Hz, 1H, C 9 -H) 2.10 (dd, J = 13.0, 9.1 Hz, 1H , C 9 -H) 2.49 (dd, J = 13.9, 2.4 Hz, 1H, C 12 -H) 2.51 (s, 3H, = N-CH 3 ) 2.63 (dddd, J = 9.1, 8.8, 7.6, 6.2 Hz , 1H, C 10 -H) 2.66 (dd, J = 13.9, 11.1 Hz, 1H, C 12 -H) 2.91 (dd, J = 11.1, 2.4 Hz, 1H, C 11a -H) 2.99 (s, 1H, C 11 -H) 3.42 (dd, J = 10.6, 6.9 Hz, 1H, C 5 -C H 2 OH) 3.43 (dd, J = 6.5, 2.7 Hz, 1H, C 8 -H) 3.56 (dd, J = 10.6, 8.8 Hz, 1H, C 10 -C H 2 OH) 3.62 (dd, J = 10.6, 7.6 Hz, 1H, C 10 -C H 2 OH) 3.76 (dd, J = 10.6, 2.6 Hz, 1H, C 5 -C H 2 OH) 3.83 (s, 3H, -OCH 3 ) 4.20 (dd, J = 6.9, 2.6 Hz, 1H, C 5 -H) 4.30 (d, J = 2.7 Hz, 1H, C 7 -H ) 6.72 (d, J = 8.0 Hz, 1H, C 3 -H) 6.82 (d, J = 8.0 Hz, 1H, C 1 -H) 7.14 (t, J = 8.0 Hz, 1H, C 2 -H) MS (m / z) 343 (M + ), 312 (M-CH 2 OH + ) HRMS (m / z) M + (C 19 H 25 N 3 O 3 ) Measured value 343.1919 Calculation Value 343.1894
【００５６】実施例４Example 4
【００５７】[0057]
【化１３】 [Chemical 13]
【００５８】（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１
１ａＳ）−５−ベンゾイルオキシメチル−７−シアノ−
１０−ヒドロキシメチル−４−メトキシ−１３−メチル
−５，７，８，９，１０，１１，１１ａ，１２−オクタ
ヒドロ−８，１１−イミノアゼピノ［１，２−ｂ］イソ
キノリン（１７．５ｍｇ， ０．０３９ｍｍｏｌ）を塩
化メチレン（１．０ｍｌ）に溶解し、トリアセトキシペ
ルヨージナン（Dess-Martin試薬）（３３．０ｍｇ，
０．０７８ｍｍｏｌ）を０゜ Ｃで加え、室温で２時間攪
拌した。反応混合物に１０％チオ硫酸ナトリウム水溶液
（１０ｍｌ）およびエーテル（１０ｍｌ）を加え分液
後、水層をエーテル（１０ｍｌ）で抽出した。有機層は
まとめて飽和炭酸水素ナトリウム水溶液（１０ｍｌ）で
洗浄した後、無水硫酸ナトリウムで乾燥し、溶媒を留去
し、残渣を分取用シリカゲル薄層クロマトグラフィー
（ヘキサン：酢酸エチル＝１：１）にて精製し（５Ｒ，
７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａＳ）−５−ベンゾ
イルオキシメチル−７−シアノ−１０−ホルミル−４−
メトキシ−１３−メチル−５，７，８，９，１０，１
１，１１ａ，１２−オクタヒドロ−８，１１−イミノア
ゼピノ［１，２−ｂ］イソキノリンを白色アモルファス
粉末（１１．０ｍｇ， ６３％）として得た。(5R, 7R, 8S, 10R, 11R, 1
1aS) -5-Benzoyloxymethyl-7-cyano-
10-Hydroxymethyl-4-methoxy-13-methyl-5,7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline (17.5 mg, 0 0.039 mmol) was dissolved in methylene chloride (1.0 ml), and triacetoxy periodinane (Dess-Martin reagent) (33.0 mg,
0.078 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. A 10% sodium thiosulfate aqueous solution (10 ml) and ether (10 ml) were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with ether (10 ml). The organic layers were washed together with a saturated aqueous solution of sodium hydrogen carbonate (10 ml), dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to preparative silica gel thin layer chromatography (hexane: ethyl acetate = 1: 1). )) (5R,
7R, 8S, 10R, 11R, 11aS) -5-Benzoyloxymethyl-7-cyano-10-formyl-4-
Methoxy-13-methyl-5,7,8,9,10,1
1,11a, 12-Octahydro-8,11-iminoazepino [1,2-b] isoquinoline was obtained as a white amorphous powder (11.0 mg, 63%).
【００５９】 [α]D 20 = +2.1゜ (c= 0.83, CHCl3) IR (neat, cm-1) 3010, 2940, 2900, 2830, 2700, 2220, 1710, 1590, 14
70, 1460, 1270, 1110, 1100, 1070, 750, 7101 H NMR (400MHz, C6D6) δ: 1.63 (dd, J= 13.2, 9.8 Hz, 1H, C9-H) 1.73 (s, 3H, =N-CH3) 1.82 (ddd, J= 13.2, 6.3, 5.6 Hz, 1H, C9-H) 2.04 (dd, J= 14.8, 2.4 Hz, 1H, C12-H) 2.26 (dd, J= 14.8, 11.9 Hz, 1H, C12-H) 2.40 (dd, J= 9.8, 5.6 Hz, 1H, C10-H) 2.62 (dd, J= 6.3, 2.8 Hz, 1H, C8-H) 2.86 (s, 1H, C11-H) 3.00 (dd, J= 11.9, 2.4 Hz, 1H, C11a-H) 3.12 (s, 3H, -OCH3) 3.54 (d, J= 2.8 Hz, 1H, C7-H) 4.36 (dd, J= 10.9, 4.2 Hz, 1H, -CH 2OBz) 4.72 (dd, J= 4.2, 3.1 Hz, 1H, C5-H) 4.78 (dd, J= 10.9, 3.1 Hz, 1H, -CH 2OBz) 6.36 (d, J= 8.0 Hz, 1H, C3-H) 6.59 (d, J= 8.0 Hz, 1H, C1-H) 6.93-7.05 (m, 3H, -OCOC6H5) 7.03 (t, J= 8.0 Hz, 1H, C2-H) 7.94-7.99 (m, 2H, -OCOC6H5) 9.16 (s, 1H, -CHO) MS (m/z) 445 (M+), 310 (M-CH2OBz+) HRMS (m/z) M+ (C26H27N3O4) 測定値 445.1997 計算値 445.1999[Α] D 20 = + 2.1 ° (c = 0.83, CHCl 3 ) IR (neat, cm −1 ) 3010, 2940, 2900, 2830, 2700, 2220, 1710, 1590, 14
70, 1460, 1270, 1110, 1100, 1070, 750, 710 1 H NMR (400MHz, C 6 D 6 ) δ: 1.63 (dd, J = 13.2, 9.8 Hz, 1H, C 9 -H) 1.73 (s, 3H, = N-CH 3 ) 1.82 (ddd, J = 13.2, 6.3, 5.6 Hz, 1H, C 9 -H) 2.04 (dd, J = 14.8, 2.4 Hz, 1H, C 12 -H) 2.26 (dd, J = 14.8, 11.9 Hz, 1H, C 12 -H) 2.40 (dd, J = 9.8, 5.6 Hz, 1H, C 10 -H) 2.62 (dd, J = 6.3, 2.8 Hz, 1H, C 8 -H) 2.86 (s, 1H, C 11 -H) 3.00 (dd, J = 11.9, 2.4 Hz, 1H, C 11a -H) 3.12 (s, 3H, -OCH 3 ) 3.54 (d, J = 2.8 Hz, 1H, C 7 -H) 4.36 (dd, J = 10.9, 4.2 Hz, 1H, -C H 2 OBz) 4.72 (dd, J = 4.2, 3.1 Hz, 1H, C 5 -H) 4.78 (dd, J = 10.9, 3.1 Hz, 1H, -C H 2 OBz) 6.36 (d, J = 8.0 Hz, 1H, C 3 -H) 6.59 (d, J = 8.0 Hz, 1H, C 1 -H) 6.93-7.05 (m, 3H , -OCOC 6 H 5 ) 7.03 (t, J = 8.0 Hz, 1H, C 2 -H) 7.94-7.99 (m, 2H, -OCOC 6 H 5 ) 9.16 (s, 1H, -CHO) MS (m / z) 445 (M + ), 310 (M-CH 2 OBz + ) HRMS (m / z) M + (C 26 H 27 N 3 O 4 ) Measured value 445.1997 Calculated value 445.1999
【００３５】実施例５Example 5
【化１４】 （５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａＳ）−５
−アセトキシメチル−７−シアノ−１０−ヒドロキシメ
チル−４−メトキシ−１３−メチル−５，７，８，９，
１０，１１，１１ａ，１２−オクタヒドロ−８，１１−
イミノアゼピノ［１，２−ｂ］イソキノリン（５２．５
ｍｇ，０．１４ｍｍｏｌ）をピリジン（２．０ｍｌ）に
溶解し、無水酢酸（６４．５μｌ， ０．６８ｍｍｏ
ｌ）を加え、室温にて４時間攪拌した。反応混合物に酢
酸エチル（１５ｍｌ）および飽和炭酸水素ナトリウム水
溶液（１０ｍｌ）を加え分液後、水層を酢酸エチル（１
５ｍｌ）で抽出した。有機層は合わせて無水硫酸ナトリ
ウムで乾燥後、溶媒を留去し、残渣を分取用シリカゲル
薄層クロマトグラフィー（ヘキサン：酢酸エチル＝２：
３ ｖ／ｖ）にて精製し（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，
１１Ｒ，１１ａＳ）−５，１０−ビス（アセトキシメチ
ル）−７−シアノ−４−メトキシ−１３−メチル−５，
７，８，９，１０，１１，１１ａ，１２−オクタヒドロ
−８，１１−イミノアゼピノ［１，２−ｂ］イソキノリ
ンを白色アモルファス粉末（５７．０ｍｇ， ９８％）
として得た。[Chemical 14] (5R, 7R, 8S, 10R, 11R, 11aS) -5
-Acetoxymethyl-7-cyano-10-hydroxymethyl-4-methoxy-13-methyl-5,7,8,9,
10,11,11a, 12-octahydro-8,11-
Iminoazepino [1,2-b] isoquinoline (52.5
mg, 0.14 mmol) was dissolved in pyridine (2.0 ml), and acetic anhydride (64.5 μl, 0.68 mmo)
1) was added, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate (15 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml) were added to the reaction mixture, and the layers were separated.
5 ml). The organic layers were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was subjected to preparative silica gel thin layer chromatography (hexane: ethyl acetate = 2:
3 v / v) and purified (5R, 7R, 8S, 10R,
11R, 11aS) -5,10-Bis (acetoxymethyl) -7-cyano-4-methoxy-13-methyl-5.
White amorphous powder of 7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline (57.0 mg, 98%)
Got as.
【００６０】 [α]D 20 = +16.2゜ (c= 1.18, CHCl3) IR (neat, cm-1) 2930, 2830, 2250, 1735, 1590, 1470, 1380, 1260, 1230, 1040, 910, 780, 7101 H NMR (400MHz, C6D6) δ: 1.34 (ddd, J= 12.9, 6.4, 6.1 Hz, 1H, C9-H) 1.65 (s, 3H, -OCOCH3) 1.68 (dd, J= 12.9, 9.1 Hz, 1H, C9-H) 1.69 (s, 3H, -OCOCH3) 2.08 (dd, J= 14.7, 2.4 Hz, 1H, C12-H) 2.20 (s, 3H, =N-CH3) 2.44 (dd, J= 14.7, 10.6 Hz, 1H, C12-H) 2.47 (dddd, J= 9.1, 8.5, 8.0, 6.1 Hz, 1H, C10-H) 2.48 (s, 1H, C11-H) 2.81 (dd, J= 6.4, 2.6 Hz, 1H, C8-H) 3.07 (dd, J= 10.6, 2.4 Hz, 1H, C11a-H) 3.13 (s, 3H, -OCH3) 3.44 (d, J= 2.6 Hz, 1H, C7-H) 3.86 (dd, J= 10.7, 8.5 Hz, 1H, C10-CH 2OAc) 3.94 (dd, J= 10.7, 8.0 Hz, 1H, C10-CH 2OAc) 4.08 (dd, J= 11.5, 4.8 Hz, 1H, C5-CH 2OAc) 4.59 (dd, J= 11.5, 3.0 Hz, 1H, C5-CH 2OAc) 4.60 (dd, J= 4.8, 3.0 Hz, 1H, C5-H) 6.33 (d, J= 8.0 Hz, 1H, C3-H) 6.60 (d, J= 8.0 Hz, 1H, C1-H) 7.01 (t, J= 8.0 Hz, 1H, C2-H) MS (m/z) 427 (M+), 354 (M-CH2OAc+) HRMS (m/z) M+ (C23H29N3O5) 測定値 427.2104 計算値 427.2104[Α] D 20 = + 16.2 ° (c = 1.18, CHCl 3 ) IR (neat, cm −1 ) 2930, 2830, 2250, 1735, 1590, 1470, 1380, 1260, 1230, 1040, 910, 780, 710 1 H NMR (400MHz, C 6 D 6 ) δ: 1.34 (ddd, J = 12.9, 6.4, 6.1 Hz, 1H, C 9 -H) 1.65 (s, 3H, -OCOCH 3 ) 1.68 (dd, J = 12.9, 9.1 Hz, 1H, C 9 -H) 1.69 (s, 3H, -OCOCH 3 ) 2.08 (dd, J = 14.7, 2.4 Hz, 1H, C 12 -H) 2.20 (s, 3H, = N -CH 3 ) 2.44 (dd, J = 14.7, 10.6 Hz, 1H, C 12 -H) 2.47 (dddd, J = 9.1, 8.5, 8.0, 6.1 Hz, 1H, C 10 -H) 2.48 (s, 1H, C 11 -H) 2.81 (dd, J = 6.4, 2.6 Hz, 1H, C 8 -H) 3.07 (dd, J = 10.6, 2.4 Hz, 1H, C 11a -H) 3.13 (s, 3H, -OCH 3 ) 3.44 (d, J = 2.6 Hz, 1H, C 7 -H) 3.86 (dd, J = 10.7, 8.5 Hz, 1H, C 10 -C H 2 OAc) 3.94 (dd, J = 10.7, 8.0 Hz, 1H , C 10 -C H 2 OAc) 4.08 (dd, J = 11.5, 4.8 Hz, 1H, C 5 -C H 2 OAc) 4.59 (dd, J = 11.5, 3.0 Hz, 1H, C 5 -C H 2 OAc ) 4.60 (dd, J = 4.8, 3.0 Hz, 1H, C 5 -H) 6.33 (d, J = 8.0 Hz, 1H, C 3 -H) 6.60 (d, J = 8.0 Hz, 1H, C 1 -H) ) 7.01 (t, J = 8.0 Hz, 1H, C 2 -H) MS (m / z) 427 (M + ), 354 (M-CH 2 OAc + ) HRMS (m / z) M + (C 23 H 29 N 3 O 5 ) Measured value 427.2104 Calculated value 427.2104
【００６１】実施例６Example 6
【００６２】[0062]
【化１５】 [Chemical 15]
【００６３】（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１
１ａＳ）−５−アセトキシメチル−７−シアノ−１０−
ヒドロキシメチル−４−メトキシ−１３−メチル−５，
７，８，９，１０，１１，１１ａ，１２−オクタヒドロ
−８，１１−イミノアゼピノ［１，２−ｂ］イソキノリ
ン（６０．０ｍｇ， ０．１６ｍｍｏｌ）をピリジン
（２．０ｍｌ）に溶解し、塩化ベンゾイル（３５．０μ
ｌ， ０．３０ｍｍｏｌ）を０゜ Ｃで加え、室温で３０
分攪拌した。反応混合物に酢酸エチル（１５ｍｌ）およ
び飽和炭酸水素ナトリウム水溶液（１５ｍｌ）を加え分
液後、水層を酢酸エチル（１５ｍｌ）で抽出した。有機
層は合わせて無水硫酸ナトリウムで乾燥後、溶媒を留去
し、残渣を分取用シリカゲル薄層クロマトグラフィー
（ヘキサン：酢酸エチル＝１：１）にて精製し、（５
Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａＳ）−５−ア
セトキシメチル−１０−ベンゾイルオキシメチル−７−
シアノ−４−メトキシ−１３−メチル−５，７，８，
９，１０，１１，１１ａ，１２−オクタヒドロ−８，１
１−イミノアゼピノ［１，２−ｂ］イソキノリンを白色
アモルファス粉末（７５．２ｍｇ， ９９％）として得
た。(5R, 7R, 8S, 10R, 11R, 1
1aS) -5-acetoxymethyl-7-cyano-10-
Hydroxymethyl-4-methoxy-13-methyl-5
7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline (60.0 mg, 0.16 mmol) was dissolved in pyridine (2.0 ml) and salified. Benzoyl (35.0μ
1, 0.30 mmol) at 0 ° C., and added at room temperature to 30
Stir for minutes. Ethyl acetate (15 ml) and saturated aqueous sodium hydrogen carbonate solution (15 ml) were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with ethyl acetate (15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by preparative silica gel thin layer chromatography (hexane: ethyl acetate = 1: 1).
R, 7R, 8S, 10R, 11R, 11aS) -5-acetoxymethyl-10-benzoyloxymethyl-7-
Cyano-4-methoxy-13-methyl-5,7,8,
9,10,11,11a, 12-octahydro-8,1
1-Iminoazepino [1,2-b] isoquinoline was obtained as a white amorphous powder (75.2 mg, 99%).
【００６４】 [α]D 20 = +14.8゜ (c= 1.23, CHCl3) IR (neat, cm-1) 2940, 2830, 2220, 1730, 1715, 1590, 1470, 1450, 1380, 1260, 1225, 1100, 750, 7101 H NMR (400MHz, C6D6) δ: 1.38 (ddd, J= 12.9, 6.3, 6.1 Hz, 1H, C9-H) 1.65 (s, 3H, -OCOCH3) 1.73 (dd, J= 12.9, 8.9 Hz, 1H, C9-H) 2.08 (dd, J= 14.5, 2.3 Hz, 1H, C12-H) 2.23 (s, 3H, =N-CH3) 2.50 (dd, J= 14.5, 12.0 Hz, 1H, C12-H) 2.58 (s, 1H, C11-H) 2.61 (dddd, J= 9.7, 8.9, 7.8, 6.1 Hz, 1H, C10-H) 2.83 (dd, J= 6.3, 2.6 Hz, 1H, C8-H) 3.07 (dd, J= 12.0, 2.3 Hz, 1H, C11a-H) 3.12 (s, 3H, -OCH3) 3.48 (d, J= 2.6 Hz, 1H, C7-H) 4.09 (dd, J= 11.5, 4.7 Hz, 1H, -CH 2OAc) 4.10 (dd, J= 10.6, 9.7 Hz, 1H, -CH 2OBz) 4.18 (dd, J= 10.6, 7.8 Hz, 1H, -CH 2OBz) 4.59 (dd, J= 11.5, 3.0 Hz, 1H, -CH 2OAc) 4.60 (dd, J= 4.7, 3.0 Hz, 1H, C5-H) 6.32 (d, J= 8.0 Hz, 1H, C3-H) 6.52 (d, J= 8.0 Hz, 1H, C1-H) 6.98 (t, J= 8.0 Hz, 1H, C2-H) 7.06-7.13 (m, 3H, -OCOC6H5) 8.14-8.20 (m, 2H, -OCOC6H5) MS (m/z) 489 (M+), 416 (M-CH2OAc+) HRMS (m/z) M+ (C28H31N3O5) 測定値 489.2250 計算値 489.2261[Α] D 20 = + 14.8 ° (c = 1.23, CHCl 3 ) IR (neat, cm −1 ) 2940, 2830, 2220, 1730, 1715, 1590, 1470, 1450, 1380, 1260, 1225, 1100, 750, 710 1 H NMR (400MHz, C 6 D 6 ) δ: 1.38 (ddd, J = 12.9, 6.3, 6.1 Hz, 1H, C 9 -H) 1.65 (s, 3H, -OCOCH 3 ) 1.73 ( dd, J = 12.9, 8.9 Hz, 1H, C 9 -H) 2.08 (dd, J = 14.5, 2.3 Hz, 1H, C 12 -H) 2.23 (s, 3H, = N-CH 3 ) 2.50 (dd, J = 14.5, 12.0 Hz, 1H, C 12 -H) 2.58 (s, 1H, C 11 -H) 2.61 (dddd, J = 9.7, 8.9, 7.8, 6.1 Hz, 1H, C 10 -H) 2.83 (dd , J = 6.3, 2.6 Hz, 1H, C 8 -H) 3.07 (dd, J = 12.0, 2.3 Hz, 1H, C 11a -H) 3.12 (s, 3H, -OCH 3 ) 3.48 (d, J = 2.6 Hz, 1H, C 7 -H) 4.09 (dd, J = 11.5, 4.7 Hz, 1H, -C H 2 OAc) 4.10 (dd, J = 10.6, 9.7 Hz, 1H, -C H 2 OBz) 4.18 (dd , J = 10.6, 7.8 Hz, 1H, -C H 2 OBz) 4.59 (dd, J = 11.5, 3.0 Hz, 1H, -C H 2 OAc) 4.60 (dd, J = 4.7, 3.0 Hz, 1H, C 5 -H) 6.32 (d, J = 8.0 Hz, 1H, C 3 -H) 6.52 (d, J = 8.0 Hz, 1H, C 1 -H) 6.98 (t, J = 8.0 Hz, 1H, C 2 -H ) 7.06-7.13 (m, 3H, -OCOC 6 H 5 ) 8.14-8.20 (m, 2H, -OCOC 6 H 5 ) MS (m / z) 489 (M + ), 41 6 (M-CH 2 OAc + ) HRMS (m / z) M + (C 28 H 31 N 3 O 5 ) Measured value 489.2250 Calculated value 489.2261
【００６５】実施例７Example 7
【００６６】[0066]
【化１６】 [Chemical 16]
【００６７】（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１
１ａＳ）−５−ベンゾイルオキシメチル−７−シアノ−
１０−ヒドロキシメチル−４−メトキシ−１３−メチル
−５，７，８，９，１０，１１，１１ａ，１２−オクタ
ヒドロ−８，１１−イミノアゼピノ［１，２−ｂ］イソ
キノリン（５５．０ｍｇ， ０．１２ｍｍｏｌ）をピリ
ジン（１．０ｍｌ）に溶解し、無水酢酸（５８．０μ
ｌ， ０．６２ｍｍｏｌ）を加え、室温にて１時間攪拌
した。反応混合物にエーテル（１０ｍｌ）及び飽和炭酸
水素ナトリウム水溶液（１０ｍｌ）を加え分液後、水層
をエーテル（１０ｍｌ）で抽出した。有機層はまとめて
無水硫酸ナトリウムで乾燥後、溶媒を留去し、残渣を分
取用シリカゲル薄層クロマトグラフィー（ヘキサン：酢
酸エチル＝１：１）にて精製し（５Ｒ，７Ｒ，８Ｓ，１
０Ｒ，１１Ｒ，１１ａＳ）−１０−アセトキシメチル−
５−ベンゾイルオキシメチル−７−シアノ−４−メトキ
シ−１３−メチル−５，７，８，９，１０，１１，１１
ａ，１２−オクタヒドロ−８，１１−イミノアゼピノ
［１，２−ｂ］イソキノリンを白色アモルファス粉末
（４０．９ｍｇ， ６８％）として得た。(5R, 7R, 8S, 10R, 11R, 1
1aS) -5-Benzoyloxymethyl-7-cyano-
10-Hydroxymethyl-4-methoxy-13-methyl-5,7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline (55.0 mg, 0 .12 mmol) was dissolved in pyridine (1.0 ml) and acetic anhydride (58.0 μm) was added.
1, 0.62 mmol) was added and the mixture was stirred at room temperature for 1 hour. Ether (10 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml) were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with ether (10 ml). The organic layers are combined, dried over anhydrous sodium sulfate, the solvent is distilled off, and the residue is purified by preparative silica gel thin layer chromatography (hexane: ethyl acetate = 1: 1) (5R, 7R, 8S, 1).
0R, 11R, 11aS) -10-acetoxymethyl-
5-benzoyloxymethyl-7-cyano-4-methoxy-13-methyl-5,7,8,9,10,11,11
a, 12-Octahydro-8,11-iminoazepino [1,2-b] isoquinoline was obtained as a white amorphous powder (40.9 mg, 68%).
【００６８】 [α]D 20 = -7.7゜ (c= 0.32, CHCl3) IR (neat, cm-1) 2940, 2900, 2830, 2250, 1740, 1720, 1590, 1470, 1450, 1380, 1260, 1110, 1100, 910, 730, 7101 H NMR (400MHz, C6D6) δ: 1.29 (ddd, J= 13.0, 6.3, 5.8 Hz, 1H, C9-H) 1.62 (s, 3H, -OCOCH3) 1.73 (dd, J= 13.0, 9.0 Hz, 1H, C9-H) 2.04 (dd, J= 14.8, 2.3 Hz, 1H, C12-H) 2.15 (s, 3H, =N-CH3) 2.24 (dddd, J= 9.0, 8.2, 7.9, 5.8 Hz, 1H, C10-H) 2.40 (s, 1H, C11-H) 2.44 (dd, J= 14.8, 11.9 Hz, 1H, C12-H) 2.76 (dd, J= 6.3, 2.6 Hz, 1H, C8-H) 3.06 (dd, J= 11.9, 2.3 Hz, 1H, C11a-H) 3.13 (s, 3H, -OCH3) 3.52 (d, J= 2.6 Hz, 1H, C7-H) 3.76 (dd, J= 10.7, 8.2 Hz, 1H, -CH 2OAc) 3.79 (dd, J= 10.7, 7.9 Hz, 1H, -CH 2OAc) 4.43 (dd, J= 11.0, 3.6 Hz, 1H, -CH 2OBz) 4.73 (dd, J= 3.6, 3.1 Hz, 1H, C5-H) 4.82 (dd, J= 11.0, 3.1 Hz, 1H, -CH 2OBz) 6.36 (d, J= 8.0 Hz, 1H, C3-H) 6.61 (d, J= 8.0 Hz, 1H, C1-H) 6.93-7.07 (m, 4H, C2-H and 3H of -OCOC6H5) 7.97-8.04 (m, 2H, -OCOC6H5) MS (m/z) 489 (M+), 354 (M-CH2OBz+) HRMS (m/z) M+ (C28H31N3O5) 測定値 489.2270 計算値 489.2262[Α] D 20 = -7.7 ° (c = 0.32, CHCl 3 ) IR (neat, cm -1 ) 2940, 2900, 2830, 2250, 1740, 1720, 1590, 1470, 1450, 1380, 1260, 1110, 1100, 910, 730, 710 1 H NMR (400MHz, C 6 D 6 ) δ: 1.29 (ddd, J = 13.0, 6.3, 5.8 Hz, 1H, C 9 -H) 1.62 (s, 3H, -OCOCH 3 ) 1.73 (dd, J = 13.0, 9.0 Hz, 1H, C 9 -H) 2.04 (dd, J = 14.8, 2.3 Hz, 1H, C 12 -H) 2.15 (s, 3H, = N-CH 3 ) 2.24 (dddd, J = 9.0, 8.2, 7.9, 5.8 Hz, 1H, C 10 -H) 2.40 (s, 1H, C 11 -H) 2.44 (dd, J = 14.8, 11.9 Hz, 1H, C 12 -H) ) 2.76 (dd, J = 6.3, 2.6 Hz, 1H, C 8 -H) 3.06 (dd, J = 11.9, 2.3 Hz, 1H, C 11a -H) 3.13 (s, 3H, -OCH 3 ) 3.52 (d , J = 2.6 Hz, 1H, C 7 -H) 3.76 (dd, J = 10.7, 8.2 Hz, 1H, -C H 2 OAc) 3.79 (dd, J = 10.7, 7.9 Hz, 1H, -C H 2 OAc ) 4.43 (dd, J = 11.0, 3.6 Hz, 1H, -C H 2 OBz) 4.73 (dd, J = 3.6, 3.1 Hz, 1H, C 5 -H) 4.82 (dd, J = 11.0, 3.1 Hz, 1H , -C H 2 OBz) 6.36 (d, J = 8.0 Hz, 1H, C 3 -H) 6.61 (d, J = 8.0 Hz, 1H, C 1 -H) 6.93-7.07 (m, 4H, C 2- H and 3H of -OCOC 6 H 5 ) 7.97-8.04 (m, 2H, -OCOC 6 H 5 ) MS (m / z) 489 (M + ), 354 (M- CH 2 OBz + ) HRMS (m / z) M + (C 28 H 31 N 3 O 5 ) Measured value 489.2270 Calculated value 489.2262
【００６９】実施例８Example 8
【００７０】[0070]
【化１７】 [Chemical 17]
【００７１】（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１
１ａＳ）−５−ベンゾイルオキシメチル−７−シアノ−
１０−ヒドロキシメチル−４−メトキシ−１３−メチル
−５，７，８，９，１０，１１，１１ａ，１２−オクタ
ヒドロ−８，１１−イミノアゼピノ［１，２−ｂ］イソ
キノリン（６１．０ｍｇ， ０．１４ｍｍｏｌ）をピリ
ジン（１．０ｍｌ）に溶解し、０゜ Ｃにて塩化ベンゾイ
ル（３２．０μｌ，０．２８ｍｍｏｌ）を加え、室温で
３０分攪拌した。反応混合物にエーテル（１０ｍｌ）及
び飽和炭酸水素ナトリウム水溶液（１０ｍｌ）を加え分
液後、水層をエーテル（１０ｍｌ）で抽出した。有機層
は合わせて無水硫酸ナトリウムで乾燥後、溶媒を留去
し、残渣を分取用シリカゲル薄層クロマトグラフィー
（ヘキサン：酢酸エチル＝１：１）にて精製し（５Ｒ，
７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａＳ）−５，１０−
ビス（ベンゾイルオキシメチル）−７−シアノ−４−メ
トキシ−１３−メチル−５，７，８，９，１０，１１，
１１ａ，１２−オクタヒドロ−８，１１−イミノアゼピ
ノ［１，２−ｂ］イソキノリンを白色アモルファス粉末
（６２．７ｍｇ， ８４％）として得た。(5R, 7R, 8S, 10R, 11R, 1
1aS) -5-Benzoyloxymethyl-7-cyano-
10-Hydroxymethyl-4-methoxy-13-methyl-5,7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline (61.0 mg, 0 0.14 mmol) was dissolved in pyridine (1.0 ml), benzoyl chloride (32.0 μl, 0.28 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Ether (10 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml) were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with ether (10 ml). The combined organic layers were dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by preparative silica gel thin layer chromatography (hexane: ethyl acetate = 1: 1) (5R,
7R, 8S, 10R, 11R, 11aS) -5, 10-
Bis (benzoyloxymethyl) -7-cyano-4-methoxy-13-methyl-5,7,8,9,10,11,
11a, 12-Octahydro-8,11-iminoazepino [1,2-b] isoquinoline was obtained as a white amorphous powder (62.7 mg, 84%).
【００７２】 [α]D 20 = -5.8゜ (c= 0.24, CHCl3) IR (neat, cm-1) 2930, 2830, 2250, 1710, 1590, 1470, 1450, 1310, 1270, 1110, 1070, 910, 730, 7101 H NMR (400MHz, C6D6) δ: 1.34 (ddd, J= 12.9, 6.3, 5.9 Hz, 1H, C9-H) 1.79 (dd, J= 12.9, 9.0 Hz, 1H, C9-H) 2.03 (dd, J= 14.8, 2.4 Hz, 1H, C12-H) 2.17 (s, 3H, =N-CH3) 2.37 (dddd, J= 9.0, 8.8, 7.8, 5.9 Hz, 1H, C10-H) 2.47 (s, 1H, C11-H) 2.48 (dd, J= 14.8, 11.9 Hz, 1H, C12-H) 2.78 (dd, J= 6.3, 2.5 Hz, 1H, C8-H) 3.06 (dd, J= 11.9, 2.4 Hz, 1H, C11a-H) 3.13 (s, 3H, -OCH3) 3.54 (d, J= 2.5 Hz, 1H, C7-H) 3.96 (dd, J= 10.6, 7.8 Hz, 1H, C10-CH 2OBz) 4.01 (dd, J= 10.6, 8.8 Hz, 1H, C10-CH 2OBz) 4.42 (dd, J= 11.0, 3.6 Hz, 1H, C5-CH 2OBz) 4.73 (dd, J= 3.6, 3.1 Hz, 1H, C5-H) 4.87 (dd, J= 11.0, 3.1 Hz, 1H, C5-CH 2OBz) 6.37 (d, J= 8.0 Hz, 1H, C3-H) 6.57 (d, J= 8.0 Hz, 1H, C1-H) 7.06 (t, J= 8.0 Hz, 1H, C2-H) 6.90-7.20 (m, 6H, -OCOC6H5) 7.98-8.04 (m, 2H, -OCOC6H5) 8.06-8.13 (m, 2H, -OCOC6H5) MS (m/z) 551 (M+), 416 (M-CH20Bz+) HRMS (m/z) M+ (C33H33N3O5) 測定値 551.2413 計算値 551.2417[Α] D 20 = -5.8 ° (c = 0.24, CHCl 3 ) IR (neat, cm -1 ) 2930, 2830, 2250, 1710, 1590, 1470, 1450, 1310, 1270, 1110, 1070, 910, 730, 710 1 H NMR (400MHz, C 6 D 6 ) δ: 1.34 (ddd, J = 12.9, 6.3, 5.9 Hz, 1H, C 9 -H) 1.79 (dd, J = 12.9, 9.0 Hz, 1H , C 9 -H) 2.03 (dd, J = 14.8, 2.4 Hz, 1H, C 12 -H) 2.17 (s, 3H, = N-CH 3 ) 2.37 (dddd, J = 9.0, 8.8, 7.8, 5.9 Hz , 1H, C 10 -H) 2.47 (s, 1H, C 11 -H) 2.48 (dd, J = 14.8, 11.9 Hz, 1H, C 12 -H) 2.78 (dd, J = 6.3, 2.5 Hz, 1H, C 8 -H) 3.06 (dd, J = 11.9, 2.4 Hz, 1H, C 11a -H) 3.13 (s, 3H, -OCH 3 ) 3.54 (d, J = 2.5 Hz, 1H, C 7 -H) 3.96 (dd, J = 10.6, 7.8 Hz, 1H, C 10 -C H 2 OBz) 4.01 (dd, J = 10.6, 8.8 Hz, 1H, C 10 -C H 2 OBz) 4.42 (dd, J = 11.0, 3.6 Hz, 1H, C 5 -C H 2 OBz) 4.73 (dd, J = 3.6, 3.1 Hz, 1H, C 5 -H) 4.87 (dd, J = 11.0, 3.1 Hz, 1H, C 5 -C H 2 OBz ) 6.37 (d, J = 8.0 Hz, 1H, C 3 -H) 6.57 (d, J = 8.0 Hz, 1H, C 1 -H) 7.06 (t, J = 8.0 Hz, 1H, C 2 -H) 6.90 -7.20 (m, 6H, -OCOC 6 H 5 ) 7.98-8.04 (m, 2H, -OCOC 6 H 5 ) 8.06-8.13 (m, 2H, -OCOC 6 H 5 ) MS (m / z) 551 (M + ), 416 (M-CH 2 0Bz + ) HRMS (m / z) M + (C 33 H 33 N 3 O 5 ) Measured value 551.2413 Calculated value 551.2417
【００７３】実施例９Example 9
【００７４】[0074]
【化１８】 [Chemical 18]
【００７５】（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１
１ａＳ）−５−ベンゾイルオキシメチル−７−シアノ−
１０−ヒドロキシメチル−４−メトキシ−１３−メチル
−５，７，８，９，１０，１１，１１ａ，１２−オクタ
ヒドロ−８，１１−イミノアゼピノ［１，２−ｂ］イソ
キノリン（２１．０ｍｇ， ０．０４７ｍｍｏｌ）を塩
化メチレン（１．０ｍｌ）に溶解し、トリエチルアミン
（２０．０μｌ， ０．１４ｍｍｏｌ）および塩化メタ
ンスルホニル（１０．０μｌ， ０．１３ｍｍｏｌ）を
加え、室温で１０分攪拌した。反応混合液にエーテル
（１０ｍｌ）及び飽和炭酸水素ナトリウム水溶液（１０
ｍｌ）を加え分液後、水層をエーテル（１０ｍｌ）で抽
出した。有機層はまとめて無水硫酸ナトリウムで乾燥
後、溶媒を留去し、残留物を分取用シリカゲル薄層クロ
マトグラフィー（ヘキサン：酢酸エチル＝１：１）にて
精製し（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａ
Ｓ）−５−ベンゾイルオキシメチル−７−シアノ−４−
メトキシ−１３−メチル−１０−メタンスルホニルオキ
シメチル−５，７，８，９，１０，１１，１１ａ，１２
−オクタヒドロ−８，１１−イミノアゼピノ［１，２−
ｂ］イソキノリンを無色透明のオイル（１０．４ｍｇ，
４２％）として得た。(5R, 7R, 8S, 10R, 11R, 1
1aS) -5-Benzoyloxymethyl-7-cyano-
10-Hydroxymethyl-4-methoxy-13-methyl-5,7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline (21.0 mg, 0 0.047 mmol) was dissolved in methylene chloride (1.0 ml), triethylamine (20.0 μl, 0.14 mmol) and methanesulfonyl chloride (10.0 μl, 0.13 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Ether (10 ml) and saturated aqueous sodium hydrogen carbonate solution (10
(ml) was added and the layers were separated, and the aqueous layer was extracted with ether (10 ml). The organic layers were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by preparative silica gel thin layer chromatography (hexane: ethyl acetate = 1: 1) (5R, 7R, 8S, 10R, 11R, 11a
S) -5-Benzoyloxymethyl-7-cyano-4-
Methoxy-13-methyl-10-methanesulfonyloxymethyl-5,7,8,9,10,11,11a, 12
-Octahydro-8,11-iminoazepino [1,2-
b] Isoquinoline was added as a colorless transparent oil (10.4 mg,
42%).
【００７６】 [α]D 20 = -10.5゜ (c= 0.93, CHCl3) IR (neat, cm-1) 2930, 2900, 2830, 2270, 1710, 1590, 1470, 1350, 1270, 1170, 1110, 950, 7101 H NMR (200MHz, C6D6) δ: 1.17 (ddd, J= 12.9, 6.3, 6.0 Hz, 1H, C9-H) 1.70 (dd, J= 12.9, 8.9 Hz, 1H, C9-H) 2.03 (dd, J= 14.8, 2.4 Hz, 1H, C12-H) 2.04 (s, 3H, -SO2CH3) 2.16 (s, 3H, -OCOCH3) 2.25 (ddt, J= 7.5, 6.0, 8.9 Hz, 1H, C10-H) 2.40 (dd, J= 14.8, 11.7 Hz, 1H, C12-H) 2.48 (s, 1H, C11-H) 2.75 (dd, J= 6.3, 2.4 Hz, 1H, C8-H) 3.04 (dd, J= 11.7, 2.4 Hz, 1H, C11a-H) 3.14 (s, 3H, -OCH3) 3.50 (d, J= 2.4 Hz, 1H, C7-H) 3.63 (dd, J= 9.6, 7.5 Hz, 1H, -CH 2OMs) 3.68 (dd, J= 9.6, 8.9 Hz, 1H, -CH 2OMs) 4.42 (dd, J= 10.9, 3.5 Hz, 1H, -CH 20Bz) 4.73 (dd, J= 3.5, 3.1 Hz, 1H, C5-H) 4.82 (dd, J= 10.9, 3.1 Hz, 1H, -CH 2OBz) 6.37 (d, J= 7.9 Hz, 1H, C3-H) 6.60 (d, J= 7.9 Hz, 1H, C1-H) 7.04 (t, J= 7.9 Hz, 1H, C2-H) 6.95-7.10 (m, 3H, -OCOC6H5) 7.90-8.05 (m, 2H, -OCOC6H5) MS (m/z) 525 (M+), 429 (M-CH3SO3H+), 390 (M-CH2OBz+), 294 (M-CH3SO3H-CH2OBz+) HRMS (m/z) M+ (C27H31N3O6S) 測定値 525.1916 計算値 525.1930[Α] D 20 = -10.5 ° (c = 0.93, CHCl 3 ) IR (neat, cm -1 ) 2930, 2900, 2830, 2270, 1710, 1590, 1470, 1350, 1270, 1170, 1110, 950, 710 1 H NMR (200MHz, C 6 D 6 ) δ: 1.17 (ddd, J = 12.9, 6.3, 6.0 Hz, 1H, C 9 -H) 1.70 (dd, J = 12.9, 8.9 Hz, 1H, C 9 -H) 2.03 (dd, J = 14.8, 2.4 Hz, 1H, C 12 -H) 2.04 (s, 3H, -SO 2 CH 3 ) 2.16 (s, 3H, -OCOCH 3 ) 2.25 (ddt, J = 7.5, 6.0, 8.9 Hz, 1H, C 10 -H) 2.40 (dd, J = 14.8, 11.7 Hz, 1H, C 12 -H) 2.48 (s, 1H, C 11 -H) 2.75 (dd, J = 6.3 , 2.4 Hz, 1H, C 8 -H) 3.04 (dd, J = 11.7, 2.4 Hz, 1H, C 11a -H) 3.14 (s, 3H, -OCH 3 ) 3.50 (d, J = 2.4 Hz, 1H, C 7 -H) 3.63 (dd, J = 9.6, 7.5 Hz, 1H, -C H 2 OMs) 3.68 (dd, J = 9.6, 8.9 Hz, 1H, -C H 2 OMs) 4.42 (dd, J = 10.9 , 3.5 Hz, 1H, -C H 2 0Bz) 4.73 (dd, J = 3.5, 3.1 Hz, 1H, C 5 -H) 4.82 (dd, J = 10.9, 3.1 Hz, 1H, -C H 2 OBz) 6.37 (d, J = 7.9 Hz, 1H, C 3 -H) 6.60 (d, J = 7.9 Hz, 1H, C 1 -H) 7.04 (t, J = 7.9 Hz, 1H, C 2 -H) 6.95-7.10 (m, 3H, -OCOC 6 H 5 ) 7.90-8.05 (m, 2H, -OCOC 6 H 5 ) MS (m / z) 525 (M + ), 429 (M-CH 3 S O 3 H + ), 390 (M-CH 2 OBz + ), 294 (M-CH 3 SO 3 H-CH 2 OBz + ) HRMS (m / z) M + (C 27 H 31 N 3 O 6 S) Measured value 525.1916 Calculated value 525.1930
【００７７】実施例１０Example 10
【００７８】[0078]
【化１９】 [Chemical 19]
【００７９】アルゴン雰囲気下、（５Ｒ，７Ｒ，８Ｓ，
１０Ｒ，１１Ｒ，１１ａＳ）−５−アセトキシメチル−
７−シアノ−１０−ヒドロキシメチル−４−メトキシ−
１３−メチル−５，７，８，９，１０，１１，１１ａ，
１２−オクタヒドロ−８，１１−イミノアゼピノ［１，
２−ｂ］イソキノリン（７６．１ｍｇ， ０．２０ｍｍ
ｏｌ）のジクロロメタン溶液（５．０ｍｌ）にジエチル
アミノイオウトリフロリド（７９．０μｌ， ０．６０
ｍｍｏｌ）を加え室温で１時間攪拌した。反応混合物に
水（３．０ｍｌ）を加え、ジクロロメタン（１０ｍｌで
２回）で抽出した。抽出液を無水硫酸マグネシウムで乾
燥後、溶媒を留去し、残渣をシリカゲルカラムクロマト
グラフィー（ヘキサン：酢酸エチル＝ ２：１）で精製
し、（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａＳ）
−５−アセトキシメチル−７−シアノ−１０−フロロメ
チル−４−メトキシ−１３−メチル−５，７，８，９，
１０，１１，１１ａ，１２−オクタヒドロ−８，１１−
イミノアゼピノ［１，２−ｂ］イソキノリンを淡褐色カ
ラメル（３６．７ｍｇ， ４８％）として得た。Under an argon atmosphere, (5R, 7R, 8S,
10R, 11R, 11aS) -5-acetoxymethyl-
7-Cyano-10-hydroxymethyl-4-methoxy-
13-methyl-5,7,8,9,10,11,11a,
12-octahydro-8,11-iminoazepino [1,
2-b] isoquinoline (76.1 mg, 0.20 mm
ol) in dichloromethane (5.0 ml) in diethylaminosulfur trifluoride (79.0 μl, 0.60
mmol) was added and the mixture was stirred at room temperature for 1 hour. Water (3.0 ml) was added to the reaction mixture, and the mixture was extracted with dichloromethane (twice with 10 ml). The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), (5R, 7R, 8S, 10R, 11R, 11aS).
-5-acetoxymethyl-7-cyano-10-fluoromethyl-4-methoxy-13-methyl-5,7,8,9,
10,11,11a, 12-octahydro-8,11-
Iminoazepino [1,2-b] isoquinoline was obtained as a light brown caramel (36.7 mg, 48%).
【００８０】 [α]D 20 = +12.7° (c= 0.14, CHCl3) IR (CHCl3, cm-1) 17301 H NMR (400MHz, C6D6) δ: 1.35-1.52 (2H, m, 9-H) 1.59 (3H, s, OCOCH3) 1.88 (1H, dd, J= 14.7, 2.2 Hz, 12-H) 2.12 (3H, s, =N-CH3) 2.25-2.30 (2H, m, 11-H and 12-H) 2.55 (1H, m, 8-H) 2.99 (1H, m, 11a-H) 3.13 (3H, s, -OCH3) 3.12-3.17 (1H, m, 10-H) 3.53 (1H, d, J= 2.2 Hz, 7-H) 4.10 (1H, dd, J= 11.0, 6.7 Hz, 6-H) 4.25 (1H, dd, J= 11.0, 3.2 Hz, 6-H) 4.59 (1H, dd, J= 6.7, 3.2 Hz, 5-H) 5.38-5.61 (1H, m, -CH2F) 6.33-6.60 (1H, m, -CH2F) 6.32 (1H, d, J= 8.2 Hz, 3-H) 6.55 (1H, d, J= 8.2 Hz, 1-H) 7.01 (1H, t, J= 8.2 Hz, 2-H)19 F NMR (188MHz, CDCl3, CFCl3) -154.7 ppm MS (m/z) 387 (M+), 314 (M-CH2OAc+) HRMS (m/z) M+ (C21H26FN3O3) 測定値 387.1963 計算値 387.1957[Α] D 20 = + 12.7 ° (c = 0.14, CHCl 3 ) IR (CHCl 3 , cm −1 ) 1730 1 H NMR (400 MHz, C 6 D 6 ) δ: 1.35-1.52 (2H, m , 9-H) 1.59 (3H, s, OCOCH 3 ) 1.88 (1H, dd, J = 14.7, 2.2 Hz, 12-H) 2.12 (3H, s, = N-CH 3 ) 2.25-2.30 (2H, m , 11-H and 12-H) 2.55 (1H, m, 8-H) 2.99 (1H, m, 11a-H) 3.13 (3H, s, -OCH 3 ) 3.12-3.17 (1H, m, 10-H ) 3.53 (1H, d, J = 2.2 Hz, 7-H) 4.10 (1H, dd, J = 11.0, 6.7 Hz, 6-H) 4.25 (1H, dd, J = 11.0, 3.2 Hz, 6-H) 4.59 (1H, dd, J = 6.7, 3.2 Hz, 5-H) 5.38-5.61 (1H, m, -CH 2 F) 6.33-6.60 (1H, m, -CH 2 F) 6.32 (1H, d, J = 8.2 Hz, 3-H) 6.55 (1H, d, J = 8.2 Hz, 1-H) 7.01 (1H, t, J = 8.2 Hz, 2-H) 19 F NMR (188MHz, CDCl 3 , CFCl 3 ) -154.7 ppm MS (m / z) 387 (M + ), 314 (M-CH 2 OAc + ) HRMS (m / z) M + (C 21 H 26 FN 3 O 3 ) Measured value 387.1963 Calculated value 387.1957
【００８１】試験例 （悪性腫瘍細胞増殖抑制試験） マウスリンパ性白血病細胞（Ｐ３８８）を２−ヒドロキ
シエチルジスルフィド５μＭ、硫酸カナマイシン１００
μｇ／ｍｌを添加した１０％牛胎児血清含有のＲＰＭＩ
−１６４０培地に加え、培養細胞を１ｘ１０4個／ｍｌ
に調整し、本発明の１０−置換−８，１１−イミノアゼ
ピノ［１，２−ｂ］イソキノリン誘導体［Ｉ］を所定の
濃度になるように添加し、ＣＯ2培養器（ＣＯ2 ５％，
湿度１００％， ３７℃）で４日間培養した。ＭＴＴ
比色法により生存細胞数を計測して、対照群に対する増
殖阻害率から５０％細胞増殖阻害濃度（ＩＣ50）を求め
た。その結果を表１に示す。Test Example (Malignant Tumor Cell Growth Inhibition Test) Mouse lymphocytic leukemia cells (P388) were treated with 2-hydroxyethyl disulfide 5 μM and kanamycin sulfate 100.
RPMI containing 10% fetal bovine serum supplemented with μg / ml
-1640 medium, add 1 × 10 4 cells / ml
And the 10-substituted-8,11-iminoazepino [1,2-b] isoquinoline derivative [I] of the present invention was added to a predetermined concentration, and a CO 2 incubator (CO 2 5%,
The culture was performed at 100% humidity and 37 ° C.) for 4 days. MTT
The number of surviving cells was measured by a colorimetric method, and the 50% cell growth inhibitory concentration (IC 50 ) was determined from the growth inhibition rate relative to the control group. The results are shown in Table 1.
【００８２】[0082]
【表１】 [Table 1]
【手続補正書】[Procedure amendment]
【提出日】平成５年９月１７日[Submission date] September 17, 1993
【手続補正１】[Procedure Amendment 1]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】００５４[Correction target item name] 0054
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【００５４】（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１
１ａＳ）−５−アセトキシメチル−７−シアノ−１０−
ヒドロキシメチル−４−メトキシ−１３−メチル−５，
７，８，９，１０，１１，１１ａ，１２−オクタヒドロ
−８，１１−イミノアゼピノ［１，２−ｂ］イソキノリ
ン（６４．５ｍｇ， ０．１７ｍｍｏｌ）をメタノール
（２．０ｍｌ）に溶解し、１％水酸化ナトリウム水溶液
（２．０ｍｌ）を加え、室温にて３０分攪拌した。反応
混合物に飽和食塩水（２０ｍｌ）および酢酸エチル（１
０ｍｌ）を加え分液後、水層を酢酸エチル（１０ｍｌ）
で抽出した。有機層は合わせて無水硫酸ナトリウムで乾
燥後、溶媒を留去し、残留物を分取用シリカゲル薄層ク
ロマトグラフィーにて精製し（５Ｒ，７Ｒ，８Ｓ，１０
Ｒ，１１Ｒ，１１ａＳ）−７−シアノ−５，１０−ビス
(ヒドロキシメチル)−４−メトキシ−１３−メチル−
５，７，８，９，１０，１１，１１ａ，１２−オクタヒ
ドロ−８，１１−イミノアゼピノ［１，２−ｂ］イソキ
ノリンを白色アモルファス粉末（５７．５ｍｇ， ９９
％）として得た。 (5R, 7R, 8S, 10R, 11R, 1
1aS) -5-acetoxymethyl-7-cyano-10-
Hydroxymethyl-4-methoxy-13-methyl-5
7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline (64.5 mg, 0.17 mmol) was dissolved in methanol (2.0 ml) to give 1 Aqueous sodium hydroxide solution (2.0 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added with saturated saline (20 ml) and ethyl acetate (1
(0 ml) was added and the layers were separated, and the aqueous layer was washed with ethyl acetate (10 ml).
It was extracted with. The organic layers were combined, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by preparative silica gel thin layer chromatography (5R, 7R, 8S, 10).
R, 11R, 11aS) -7-Cyano-5,10-bis
(Hydroxymethyl) -4-methoxy-13-methyl-
5,7,8,9,10,11,11a, 12-octahydro -8,11-iminoazepino [1,2-b] isoki
Norin as white amorphous powder (57.5 mg, 99
%).
【手続補正２】[Procedure Amendment 2]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】００７５[Correction target item name] 0075
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【００７５】（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１
１ａＳ）−５−ベンゾイルオキシメチル−７−シアノ−
１０−ヒドロキシメチル−４−メトキシ−１３−メチル
−５，７，８，９，１０，１１，１１ａ，１２−オクタ
ヒドロ−８，１１−イミノアゼピノ［１，２−ｂ］イソ
キノリン（２１．０ｍｇ， ０．０４７ｍｍｏｌ）を塩
化メチレン（１．０ｍｌ）に溶解し、トリエチルアミン
（２０．０μｌ， ０．１４ｍｍｏｌ）および塩化メタ
ンスルホニル（１０．０μｌ， ０．１３ｍｍｏｌ）を
加え、室温で１０分攪拌した。反応混合液にエーテル
（１０ｍｌ）及び飽和炭酸水素ナトリウム水溶液（１０
ｍｌ）を加え分液後、水層をエーテル（１０ｍｌ）で抽
出した。有機層はまとめて無水硫酸ナトリウムで乾燥
後、溶媒を留去し、残留物を分取用シリカゲル薄層クロ
マトグラフィー（ヘキサン：酢酸エチル＝１：１）にて
精製し（５Ｒ，７Ｒ，８Ｓ，１０Ｒ，１１Ｒ，１１ａ
Ｓ）−５−ベンゾイルオキシメチル−７−シアノ−１０
−メタンスルホニルオキシメチル−４−メトキシ−１３
−メチル−５，７，８，９，１０，１１，１１ａ，１２
−オクタヒドロ−８，１１−イミノアゼピノ［１，２−
ｂ］イソキノリンを無色透明のオイル（１０．４ｍｇ，
４２％）として得た。(5R, 7R, 8S, 10R, 11R, 1
1aS) -5-Benzoyloxymethyl-7-cyano-
10-Hydroxymethyl-4-methoxy-13-methyl-5,7,8,9,10,11,11a, 12-octahydro-8,11-iminoazepino [1,2-b] isoquinoline (21.0 mg, 0 0.047 mmol) was dissolved in methylene chloride (1.0 ml), triethylamine (20.0 μl, 0.14 mmol) and methanesulfonyl chloride (10.0 μl, 0.13 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Ether (10 ml) and saturated aqueous sodium hydrogen carbonate solution (10
(ml) was added and the layers were separated, and the aqueous layer was extracted with ether (10 ml). The organic layers were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by preparative silica gel thin layer chromatography (hexane: ethyl acetate = 1: 1) (5R, 7R, 8S, 10R, 11R, 11a
S) -5-Benzoyloxymethyl-7-cyano- 10
-Methanesulfonyloxymethyl-4-methoxy-13
-Methyl - 5,7,8,9,10,11,11a, 12
-Octahydro-8,11-iminoazepino [1,2-
b] Isoquinoline was added as a colorless transparent oil (10.4 mg,
42%).
Claims (1)
ミル基、ヒドロキシメチル基、アシルオキシメチル基、
スルホニルオキシメチル基、またはフロロメチル基を表
す）で表される１０−置換−８，１１−イミノアゼピノ
［１，２−ｂ］イソキノリン誘導体。1. A general formula: (In the formula, X is a hydrogen atom or an acyl group, Y is a formyl group, a hydroxymethyl group, an acyloxymethyl group,
A 10-substituted-8,11-iminoazepino [1,2-b] isoquinoline derivative represented by a sulfonyloxymethyl group or a fluoromethyl group).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33954792A JPH06157528A (en) | 1992-11-27 | 1992-11-27 | 10-substituted-8,11-iminoazepino(1,2-b)isoquinoline derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33954792A JPH06157528A (en) | 1992-11-27 | 1992-11-27 | 10-substituted-8,11-iminoazepino(1,2-b)isoquinoline derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06157528A true JPH06157528A (en) | 1994-06-03 |
Family
ID=18328507
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP33954792A Pending JPH06157528A (en) | 1992-11-27 | 1992-11-27 | 10-substituted-8,11-iminoazepino(1,2-b)isoquinoline derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06157528A (en) |
-
1992
- 1992-11-27 JP JP33954792A patent/JPH06157528A/en active Pending
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